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Novel Emerging Therapies for Erectile Dysfunction

Currently, several treatments exist for the improvement of erectile dysfunction (ED). These include medical therapies such as phosphodiesterase type 5 inhibitors (PDE5-Is), invasive methods such as intracavernosal injection therapy of vaso-active substances, vacuum erection devices, and penile prosthesis implants. However, the percentage of patients that are unresponsive to available treatments and who drop out from treatments remains high. Current evidence reveals that the pathogenesis of ED is related to multiple factors including underlying comorbidities, previous surgery, and psychological factors. Diverse approaches using novel molecular pathways or new technologies have been tested as potential therapeutic options for difficultto-treat ED populations. Melanocortin receptor agonist, a centrally acting agent, showed promising results by initiating erection without sexual stimulation in non-responders to PDE5-Is. Recent clinical and pre-clinical studies using human tissues suggested that new peripherally acting agents including the Max-K channel activator, guanylate cyclase activator, and nitric oxide donor could be potential therapies either as a monotherapy or in combination with PDE5-Is in ED patients. According to several clinical trials, regeneration therapy using stem cells showed favorable data in men with diabetic or post-prostatectomy ED. Low-intensity shock wave therapy also demonstrated promising results in patients with vasculogenic ED. There are growing evidences which suggest the efficacy of these emerging therapies, though most of the therapies still need to be validated by well-designed clinical trials. It is expected that, should their long-term safety and efficacy be proven, the emerging treatments can meet the needs of patients hitherto unresponsive to or unsatisfied by current therapies for ED.

There are various non-invasive and invasive treatments currently available to improve ED. The American Urological Association guidelines acknowledge that any treatment option may be used as a first-line therapy [16]; however, phosphodiesterase type 5 inhibitors (PDE5-Is) are the most commonly suggested and used first-line treatment option. Invasive treatment encompasses intracavernosal injection (ICI) with vaso-active substances, intraurethral suppository of prostaglandin E1 (PGE1, alprostadil), vacuum-assisted erectile device (VED), and penile prostheses [17,18]. Despite the noninvasive nature and excellent efficacy and safety of PDE5-Is, a non-negligible portion of ED patients do not respond to these drugs due to underlying comorbidities or previous surgery [17]. The high prevalence of nonor less-responders combined with the unmet needs in currently available therapies have prompted investigation toward the development of emerging treatment options. Different molecular pathways and diverse approaches must be studied to provide therapeutic options for a larger patient population. In this paper, we conduct a review of current treatments for ED and their limitations, and provide an overview of the novel treatments in development.

Phosphodiesterase 5 inhibitors
The most commonly used treatment for ED is PDE5-Is. PDE5-Is have been several beneficial effects in erectile dysfunction caused by a variety of factors. Up to 60% of patients who take PDE5-Is as first line ondemand treatment show a good response, defined as erection with sufficient rigidity for penetration [17,19]. Another study showed that 59% of ED patients with type 2 diabetes mellitus taking PDE5-Is had successful intercourse compared to 14 % of those taking a placebo [20]. Tadalafil was approved as a low dose (5 mg) daily regimen, as well as a classical on-demand regimen [21]. Both daily and on-demand dosing of tadalafil have been shown to exhibit the same efficacy [22]. However, daily regimen may increase the ability for spontaneity of sexual intercourse.
Although the expression of the PDE5 gene is highly detected in penile corpora cavernosa (CC) [23], the PDE5 gene has also been expressed in other portions of the male genital tract, as well as other organs in males, including skeletal muscle, lung, stomach, thyroid, and adrenal gland. This distribution is related to the adverse effects of PDE5-Is. The possible adverse events of this non-invasive drug therapy include myalgia, headache, heartburn, facial flushing, nasal congestion, and vision-related conditions, such as macular degeneration, retinitis pigmentosa, and non-arteritic anterior ischaemic optic neuropathy [24,25]. For PDE5-Is to work, patients with ED must have an intact molecular and nervous system pathway, as well as a degree of sexual stimulation. Therefore, PDE5-Is have shown a lack of efficacy in some disease states affecting the upstream nitric oxide (NO) pathway [25]. These disease states include diabetes with peripheral neuropathy [11,26], denervation after radical prostatectomy (RP) for prostate cancer [27], condition of damaged nerves critical for attaining erection, hypogonadal conditions, and Peyronie's disease (and its subsequent veno-occlusive disease). Therefore, there is a need for additional pharmacological treatment options for ED, especially for those patients who are unresponsive to PDE5-Is.

Intracavernosal injection
ICI is a treatment involving the injection of vasoactive substances directly into the CC at the lateral base of the penis via a small needle. These vaso-active medications include PGE1 (alprostadil), papaverine, and phentolamine. These medications can be used as a PGE1 monotherapy or as a formula combined with one or two other drugs (bi-mix of papaverine and phentolamine; tri-mix of prostaglandin E1, papaverine, and phentolamine).
ICI may be preferred in certain patients who are poor responders, cannot tolerate oral medications, or who are on medications contraindicated with EDtreating oral medication. Other ideal candidates for intracavernosal agents are patients who have damaged nerves for erection [28]. The main barrier to the use of ICI is patients' understandable fear of injecting the penis [29]. It is known that initial satisfaction rates following ICI are high, and that 94% of patients were satisfied with a successful erection with in-office titration [28,30]. However, dropout rates with ICI are also high-46% to 80% of patients abandoned treatment in the first year [31,32]. Causes of dropouts included high cost, problem of injection, lack of partner, and desire for a permanent solution [33].

Intraurethral prostaglandin E1 suppository
Intraurethral PGE1 suppository (IUS) uses a small intraurethral delivery catheter to place a PGE1 within the urethra for absorption through the CC before sexual intercourse. This is similar to alprostadil ICI, but is less invasive and less effective than ICI [28]. This route of administration may be preferred in patients who are poor responders, are contraindicated for oral medication, or have fear of injectable medications. IUS efficacy was reported to be between 45% and 65% depending on the group of enrolled patients [34,35]. IUS use for post-RP patients showed similar efficacy to sildenafil. However, the dropout rate of the IUS group was higher than that of sildenafil group [36]. The most common side effect and cause of discontinuation was penile or urethral pain [37,38]. Patients with urethral disease, such as urethral stricture, or with high risk for priapism should use IUS with caution. Adverse effects related to dose are dizziness, sweating, and hypotension, [39,40].

Vacuum erectile device
The VED is a device placed over the penis. The effect of VED on erection was reported to be over 75% and up to 90% [41,42]. Though the effect of VED on penile rehabilitation following RP remains controversial, a VED may be employed as part of a rehabilitation program to decrease the risk of corporal fibrosis and to assist with erectile function [43]. However, discontinuation rate was also high-up to 30% due to bruising, pivoting at the base of penis, decreased orgasm, problems related to constriction band including pain, and temporary change to penile sensation [44]. It may be difficult for patients with large lower abdominal fat and/or buried penis to use this device because they have a less usable penile shaft. Adverse reactions including petechiae and haematoma have been reported [45]. Caution is necessary in patients taking anti-coagulants because there is a greater risk of penile bruising.

Penile prosthesis
The penile prosthesis is a surgically implanted device which has undergone an evolution over the past 40 years, resulting in a more effective and reliable treatment for advanced erectile dysfunction which has failed to respond to other less invasive approaches or where these approaches are contraindicated or unacceptable to the patient.
The most common device implanted in penile surgery is the three-piece inflatable penile prosthesis (IPP) [46]. The 5-and 10-year overall survival of modern prosthetics is estimated to be 90.4% and 86.6%, respectively [47]. Patient satisfaction rate ranges from 90% to 100% and varies by prosthetic device [48,49]. However, IPP may be provided only to those patients who fail more conservative treatment because of its high cost, invasiveness, and myriad potential complications. Complications related to IPP implantation include infection, distal cylinder erosion, auto-inflation, pump migration, and reservoir displacement [50]. Infection is the most serious complication, but since the development of antibiotic and hydrophilic coatings, infection rate is decreasing [48].

Centrally acting treatments: melanocortin receptor activator
Melanocortins are a group of central neurochemistry peptides mediating sexual behaviors.
The initiation of erections without sexual stimulation distinguishes the mechanism of action of melanocortin agonists from the PDE5-Is. Melanotan II (MT-II) is a superpotent cyclic alpha-melanocyte-stimulating hormone analog. In a small double-blind placebo-controlled crossover study of psychogenic ED patients, eight out of ten men reported apparent erections with regard to penile rigidity and the significant duration of erection after subcutaneous injection of the MT-II (0.025 mg/ kg). Mean duration of tip rigidity of the penis (80%-100%) was 38 minutes with injection of MT-II versus 3 minutes with placebo. The most frequent side effects reported were yawning, nausea, and decreased appetite [51]. Another study indicated that the erectogenic action of MT-II was effective not only for treatment of psychogenic ED, but also for treatment of ED from variable organic risk factors [52]. These findings were also confirmed in other double-blind, placebo-controlled crossover study. Ten men with psychogenic ED and www.wjmh.org Ten men with organic ED received subcutaneous injections of MT-II. Seventeen out of 20 men reported penile erection from at least one of two injections of MT-II in the absence of visual sexual stimulation (VSS). A total of 68% of subjects with MT-II injections reported increased sexual desire (versus 19% in the placebo group). At the preferred dose (0.025 mg/kg), 13% of subjects injected with MT-II reported severe nausea [53]. Furthermore, the reported latency time of 113 minutes is quite long for a clinically useful drug. The addition of erotic stimulation could lead to a more rapid response. Based on the reported adverse effects, such as severe nausea, as well as the long latency time, investigators doubted the clinical utility of MT-II. No further clinical trials have been performed.
Bremelanotide is a carboxylated metabolite of MT-II, and was formerly known as PT-141. Bremelanotide is delivered intranasally using a disposable, single-use, metered dose delivery device. In the phase 1 study, of 32 healthy male subjects, the 10 mg and 20 mg doses of PT-141 resulted in a significantly greater duration of base rigidity ≥80%. Doses up to 20 mg PT-141 were safely administered to healthy male subjects [54]. In the phase 2A study, the administration of a 20 mg PT-141 dose led to significantly greater duration of base rigidity ≥80% compared to placebo. Mean duration of base rigidity ≥80% was about 24 minutes at 20 mg dose. The duration of onset was approximately 30 minutes. Single doses up to 20 mg were safely administrated and well-tolerated in most ED patients. The most commonly reported adverse events were flushing and nausea [54]. Another study evaluated the effect of stem cell (SC) administration of PT-141 on healthy subjects and on patients with ED who reported an inadequate response to sildenafil. The erectile response increased significantly at 4 mg and 6 mg SC doses of PT-141 with VSS [55]. Single doses up to 10 mg (healthy male subjects) and up to 6 mg (ED patients) of PT-141 were safely administered and well-tolerated. The most common adverse effects were flushing, somnolence, nausea, vomiting, headache, diaphoresis, and lower back pain [55]. In an at-home setting, the 342 ED patients who were non-responsive to sildenafil citrate were randomly divided to receive either PT-141 (10 mg) as an intranasally spray (n=172) or placebo (n=170) between 2 hours and 45 minutes before sexual activity. The efficacy of the treatment was assessed using the international index of erectile function (IIEF) score, the mean intercourse satisfaction domain, and number of weekly coitus episodes. In the bremelanotide group, 51 subjects (34%) reported significantly better results compared to placebo (9%), including ability to attain and maintain an erection sufficient to allow sexual intercourse, and greater intercourse satisfaction. Reported adverse effects were similar to other studies [56]. A study for co-administration of PT-141 and a PDE5-I was also conducted in 19 men with ED who were responders to sildenafil or vardenafil in order to evaluate an addictive or synergistic effect on erectile response. The erectile response induced by coadministration of PT-141 (7.5 mg) and sildenafil (25 mg) was significantly greater than the response elicited by administration of sildenafil alone [57]. The combination regimen was safe and well-tolerated and did not result in new adverse events or adverse events that were increased in frequency or severity compared with monotherapy [57]. Bremelanotide (Vyleesi TM ) has recently been approved in the United States for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder [58]. Given the promising erectogenic effect and safety, bremelanotide may provide an emerging treatment option to treat male ED patients, as well. However, further well-designed studies are needed to reach firm conclusions on long-term efficacy and safety for treatment of ED. The results of studies about centrally acting agents are summarized in Table 1.

Peripherally acting treatments 1) New phosphodiesterase type 5 inhibitors:
SLx-2101, phosphodiesterase type 5 inhibitor topical agent, phosphodiesterase type 5 inhibitor sublingual dispersal agent SLx-2101 is a PDE5-I currently under development. SLx-2101 is particularly interesting because it is metabolized to SLx-2081, an active metabolite. SLx-2081 extends its activity and may therefore clinically provide an even longer duration of benefit to ED patients. The half lives of SLx-2101 and SLx-2081 are 8 to 13 hours and 9 to 14 hours, respectively [59]. A clinical study suggested that a single dose of SLx-2101 was safe and tolerated in healthy volunteers, making it a candidate for once-daily dosing. RigiScan data showed positive effects at 0 to 6 hours post-dose in the absence of VSS for 10, 20, 40 and 80 mg doses and at 24 to 24.5 hours postdose in the presence of VSS for 20, 40, and 80 mg doses. ED: erectile dysfunction, PDE5-I: phosphodiesterase type 5 inhibitor.

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Single doses up to 40 mg were well-tolerated. Common side effects included minimal headache, as well as problems with visual effects at the 80 mg dose [59].
Although the efficacy of PDE5-Is was up to 80% in unselected ED patients, a reasonable number of dropouts was also reported [60]. The main reasons for discontinuation of treatment were the lack of efficacy and presence of side effects. Since the occurrence of side effects increases with both serum levels and exposure time to the drug [61], the design of a novel drug formulation by pharmacokinetic approach including bioavailability and route of administration could improve the safety and efficacy profile of the drug. Given this approach, application of a sildenafil topical cream is one of several new trials for the treatment of ED. A phase IIa study was conducted in 33 men with ED. Patients applied a single 2 g dose of SST-6006 topical cream 5% (delivering 100 mg of sildenafil) or a topical placebo to the penile shaft and glans. Though the study has been completed, the full results of this study have not yet been reported or published [62].
Another route of administration for PDE5-Is is sublingual dispersal. A formulation of oro-dispersible tablets (ODT) is quickly dispersed in the mouth and can be administered without water, making it highly useful in patients with swallowing disorders. Vardenafil ODT was first approved to treat ED by the Food and Drug Administration in 2010 [63]. However, though the ODT formulation of vardenafil increases bioavailability, the therapeutic effects and adverse events were not improved compared to those of vardenafil filmcoated tablets (FCT). A phase I clinical trial examined the pharmacokinetics of sildenafil ODT in 36 healthy subjects. Sildenafil ODT had a similar pharmacokinetic profile as the FCT form, and high fat meals reduced the rate of absorption of sildenafil compared to the film-coated form. Considering the food-drug interaction, sildenafil ODT should be taken on an empty stomach [64]. Another study conducted on ED patients showed that sildenafil oro-dispersal film (ODF) not only had the same safety and effectiveness as the FCT, but also produced higher overall satisfaction from patients [65].
A study was performed in 20 patients with psychogenic ED receiving alternatively oral FCT or sublingual ODT or ODF at an equal dosage (50 mg). The serum level of the ODF formulation increased more rapidly than those of both FCT and ODT. Compared to FCT as the reference formulation, the prevalence of headache in ODF decreased and the duration and intensity of flushing and nasal congestion were lower [66]. Recently, a phase I study of tadalafil ODF was conducted in 36 healthy men. The pharmacokinetics of the tadalafil ODF formulation was similar to those of the FCT formulation. Both ODF and FCT formulations of tadalafil were well-tolerated, and no clinically significant changes from baseline were observed [67].

2) Maxi-K channel activator
Large-conductance Ca (2+)-activated K(+) channels (maxi-K channel), located on the arterial and corporal smooth muscle, are potential options for treatment of ED. NS1619 was one of the first Maxi-K channel activators, and was studied for its therapeutic potential in smooth muscle disorders, including ED. Activation of NS1619 resulted in the recovery of erectile function in diabetic rats [68]. However, its poor response and many adverse events led to interruption of its clinical use [69]. Following the NS1619 investigations, a more selective maxi-K channel, NS11021, has been developed. NS11021 increases potassium currents in vascular smooth muscle, reduces vascular tension of penile arteries and CC strips, and induces erection in anesthetized rats. The efficacy of effect was similar to that of sildenafil [70]. A similar study conducted in human penile small arteries and NS11021 evoked pronounced relaxations that led to erectile response [71]. Currently, andolast is the only candidate drug targeting maxi-K channels for treatment of ED in clinical development. Well-designed clinical studies are needed to evaluate the treatment outcomes of andolast in ED patients.

3) Guanylate cyclase activator
PDE5-I showed a lack of efficacy in many patients with impaired pathway of NO-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal cascade. Attempting to directly delivery of sGC to smooth muscle cell, regardless of NO could offer a solution for PDE5-I unresponsive patients [72]. Activators of sGC such as BAY60-4552 and BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases. In an animal study, two-week therapy with BAY 60-2770 fully restored the decreased intracavernosal pressure (ICP) and low level of acetylcholine-induced cavernosal relaxations in obese ED mice [73].
In a study of a combination of BAY60-4552 (1 mg) and vardenafil (10 mg), PDE5-I non-responders showed downregulation of the NO/cGMP/sGC pathway compared to healthy subjects [72], and the combination therapy had synergistic effects on relaxation of human CC in PDE5-I nonresponders compared to vardenafil (20 mg) alone. However, superiority of a combination therapy over vardenafil alone could not be established.

4) Nitric oxide donors: L-arginine, glyceryl trinitrate
NO is the key mediator of erection from cavernosal nerve endings and partially from penile artery endothelial cells. L-arginine induces endothelial NO. In a phase II study, 26 ED patients treated with the combination formula (L-arginine aspartate 8 g combined with adenosine monophosphate 200 mg) noted improvements in erection hardness score (EHS) and IIEF-5 scores compared to patients treated with placebo. This drug was well-tolerated and there were no severe adverse effects [74]. In a randomized controlled trial evaluating the combination of sildenafil with Larginine orally on the treatment of ED, a combination group demonstrated improved IIEF-5 scores compared to the sildenafil only group. Except for gastritis, adverse effects did not differ between the two groups [75].
Glyceryl trinitrate (GTN) is a well-established vasodilatory agent with a comprehensive safety profile. GTN's vasodilatory action is thought to result from the release of NO in vascular smooth muscle [76]. Pharmacokinetic and pharmacodynamics studies showed that MED2005 (0.2%, GTN dose of 0.6 mg) has a relatively short half-life and a favorable safety profile [77]. In a recently conducted phase II randomized clinical trial [78], 232 patients received a treatment regimen of MED2005. IIEF scores increased significantly in the MED2005 group compared to the placebo group. The results of the global assessment questionnaire were consistent with IIEF scores. The onset of erection in 70% of patient was less than 10 minutes, and adverse events included mild headache and rhinitis. Improvements in all assessments were present only with mild ED. A European Phase III study, "FM57", is ongoing, with headline data expected at the end of 2019. The results of studies about peripherally acting agents are summarized in Table 2.

Regeneration therapy: stem cell
SC therapy is one of the most investigated emerging therapeutic methods for ED. In the last few years, several small clinical trials have been conducted to determine the safety and efficacy of SC therapy in ED patients. A single-blind study was conducted in seven men with type 2 diabetes and ED. Six of seven ED patients experienced morning erection and penile hardness by the third month after ICI of umbilical cord-derived SCs [79]. The degree of penile hardness by SC therapy only was still insufficient for effective penetration. However, after nine months, three of the seven patients actively treated with SC therapy alone agreed that the treatment had some effect on ED [79]. Haahr et al [80] performed a 6-month follow-up phase I study assessing treatment with autologous adipose-derived regenerative cells (ADRCs) in 17 men with post-RP ED. Eight of 17 subjects reported erectile response adequate for sexual intercourse [80]. The same authors [81] recently reported a 12-month follow-up study showing safety and effectiveness of treatment with ADRCs in 21 patients with post-RP ED. No serious adverse effects were observed during the 12 months of follow-up. Only 8 reversible minor events related to the liposuction were noted. IIEF-5 scores increased significantly at 6 months after treatment, and this improvement was sustained at 12 months. 38% of patients recovered erection sufficient for intercourse in the 12-month observation time. This improvement was observed in patients who had normal pre-operative erectile function and who were continent at inclusion [81]. In a phase I study to determine the effects of placental matrix-derived mesenchymal SCs (PM-MSCs), eight non-responders to ED oral therapy were enrolled and followed for 6 months. No serious adverse effects were noted. The ICI of PM-MSCs induced improvement in blood flow into the penis, which was sustained at 6 months. The penile artery peak systolic velocity improved after 6 months, while no significant changes were noted in either enddiastolic velocity or IIEF scores. Interestingly, three of eight patients recovered to response to PED5-Is after 3 months post-SC injection [82].
The safety and effect of bone marrow-derived mononuclear cells was assessed in 12 post-RP patients with vasculogenic ED [83]. Significant improvements in intercourse satisfaction and erectile function domains of IIEF-15 and EHS were noted at 6 months follow-up, and clinical benefit was sustained after one year [83]. A longer-term follow-up (mean, 62.1 months) data set collected by the same authors showed a lack of adverse events and slightly decreased erectile function score www.wjmh.org Table 2 compared with data acquired at the 12-month time point. Repeated injections may be necessary for lasting effect [84]. In a recent study in ED patients with diabetes, ICI of autologous bone marrow-derived mesenchymal SCs (BM-MSCs) was demonstrated to be safe and effective with significant improvement of IIEF-15 and EHS (IIEF-15 (p=0.04), erectile function (p=0.03), sexual desire (p=0.04), intercourse satisfaction (p=0.04), and overall satisfaction (p=0.04) [85]. Another phase I study with ICI of autologous BM-MSCs was conducted in ten ED patients (five diabetes-associated ED and five post-prostatectomy ED). The study has been completed and full results are pending [86]. The results of studies about stem cell therapy are summarized in Table 3.

Therapies using physical energies 1) Low-intensity shock wave therapy
Extracorporeal low-intensity shock wave therapy (LI-SWT) is a potential treatment option for ED. The micro-trauma to cavernosal tissue induced by LI-SWT may stimulate neovascularization and upregulate some factors associated with tissue healing and remodeling [87]. A prospective randomized, sham-controlled study was conducted on 55 patients with vasculogenic ED [88]. The study reported that clinically meaningful improvement of erectile function (international index of erectile function-erectile function [IIEF-EF] and EHS) was shown in 40.5% of the treatment group according to the minimum clinically important differences (MCID) criteria. There were no adverse effects reported. Another randomized clinical trial was conducted to assess changes in penile hemodynamics and IIEF-EF score in patients with vasculogenic ED [89]. For the IIEF-EF score, the MCID criteria for the treatment group were met by 56.7% of the treatment group at one month and by 75% at 12 months. In a more recent randomized clinical trial evaluating the effect of LI-SWT on ED among kidney-transplanted patients, similar findings were reported [90]. Kitrey et al [91] evaluated the longterm efficacy of LI-SWT in 156 ED patients. Efficacy was assessed by IIEF-EF at 6, 12, 18, and 24 months in patients with a successful outcome of LI-SWT according to the MCID at one month. During the follow-up period, clinical beneficial effect decreased from 64% at 1 month to 34% at 2 years. The efficacy lasted longer in mild forms of ED without comorbidity, such as diabetes. Meta-analyses have suggested that LI-SWT could significantly improve erectile function as evaluated by the IIEF and EHS [92,93]. Therapeutic efficacy could persist for about 3 months. Clinical outcomes were associated with number of shock waves, energy intensity, and duration of treatment [92]. Recent metaanalysis demonstrated that the mean difference of IIEF-EF score between the treatment and sham groups was 4.23 (p=0.012) at the 1-month follow-up. No significant adverse events were reported [94]. These studies suggest that LI-SWT appears to produce significant improvement of the IIEF and EHS and appears to be well-tolerated. However, setup of LI-SWT, treatment protocols, and follow-up durations were variable. There were 2 clinical trials that showed no difference between the LI-SWT group and control group [95,96]. Current evidence is promising, but still controversial. Robust evidence from additional randomized controlled trials with standardized protocols and longer-term follow-up procedures is needed. There are several ongoing randomized clinical trials that may help elucidate the role of LI-SWT in the treatment of ED along with producing a standardized treatment protocol [97]. Interestingly, a recent study suggested that the combination of SC therapy and LI-SWT may have synergistic effects in the promotion of angiogenesis and decrease in the destruction of cells [98]. More work needs to be done in this field to better understand the long-term efficacy and safety of this therapy, which still remains investigational at this time.

2) Low-intensity pulsed ultrasound
Another important form of physical therapy in micro-energy therapy is low-intensity pulsed ultrasound (LIPUS). LIPUS delivers pulsed ultrasound to target tissue at intensity less than 3 W/cm 2 . LIPUS therapy improves erectile function, as evidenced by increasing ICP and reversed pathological changes in penile erectile tissue, such as increased endothelial and smooth muscle content, as well as increased expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in a streptozotocin-induced diabetic rat model. Penile tissue showed decreased collagen and fiber changes with downregulation of transforming growth factor-β1/Smad/connective tissue growth factor signaling pathway by LIPUS [99].
In the randomized clinical trial conducted in mild to moderate ED [100], during the 12-week follow-up period, IIEF-EF score significantly increased. The response www.wjmh.org  www.wjmh.org rate in LIPUS group was 67.5%, which was 20% higher than the sham group at 3 months. For the sexual encounter profile questionnaires 3, the rate of positive answers for treatment group versus control group were met in 73.08% versus 28.95% at 12 weeks. There were no treatment-related adverse events reported. LIPUS therapy has potential as a non-invasive valuable therapy for nerve injury-induced ED. Despite promising results in animal studies, investigation of the therapeutic effect of LIPUS on ED in humans is limited. Additional high-quality clinical studies for ED are necessary. The results of studies about therapies using physical energies are summarized in Table 4.

CONCLUSIONS
Although there are several existing treatments for ED including PDE5-Is, ICI therapy of vaso-active substances, vacuum erection devices, and penile prosthesis implants, the percentage of patients that are unresponsive to or unsatisfied by the clinically available treatments remains high. In this context, there have been several scientific advances for innovative ED therapies in the last decade. According to recent clinical trials and pre-clinical studies using human tissues, a centrally acting melanocortin receptor agonist or new peripherally acting agents, including the Max-K channel activator, guanylate cyclase activator, and NO donor have shown promising results in improving erection. Also, combination of these therapies with PDE5-Is may be helpful in treating difficult-to-treat ED populations, such as PDE5-I non-responders. Recent clinical trials suggest that regeneration therapy using SCs could also be a potential candidate for treatment of difficult-totreat ED populations, such as diabetic or post-prostatectomy ED. Meanwhile, LI-SWT showed favorable results as a monotherapy or in combination with SC therapy in treating patients with vasculogenic ED. There is growing evidence suggesting efficacy of these emerging therapies, although most of the therapies need to be validated by well-designed clinical trials. It is expected that the emerging treatments can meet the needs of patients unresponsive to or unsatisfied by current therapies for ED once their long-term safety and efficacy have been confirmed. Mild to moderate ED (80=LIPUS, 40=sham treated control) The rate of patients with increased IIEF score ≥3 was 68% which was significantly higher than 20% in control group at 12 wk.
The percentage of patients with positive answers to SEP-3 (successful vaginal intercourse) were 73% at 12 wk after treatment which were significantly higher than 29% in control group.