The therapeutic effect and mechanism of low-intensity pulsed ultrasound for erectile dysfunction

Abstract

As an emerging therapeutic option for erectile dysfunction (ED), low-intensity pulsed ultrasound (LIPUS) has attracted increasing attention. The therapeutic effect of LIPUS is comparable to low-intensity extracorporeal shockwave therapy. However, the underlying mechanism of LIPUS remains unclear. We summarized the current literature to assess the efficacy of LIPUS for ED and elucidate the biological effects caused by LIPUS in different ED models. Preliminary clinical studies demonstrate that LIPUS is beneficial for ED with varying degrees of severity, and its therapeutic effect can be enhanced when combined with phosphodiesterase 5 inhibitors. Basic researches have shown that LIPUS can treat ED resulting from type 1 diabetes mellitus, cavernous nerve injury, or cavernosa injury. The underlying mechanisms involve upregulating endothelial and neuronal nitric oxide synthase expression, increasing smooth muscle and endothelium content, inhibiting cavernosal fibrosis mediated by the transforming growth factor-β1/drosophila mothers against decapentaplegic protein/connective tissue growth factor (TGF-β1/Smad/CTGF) pathway, and ameliorating oxidative stress via microtubule-associated protein 1 light chain 3 (LC3)- and Parkin-dependent mitophagy in type 1 diabetic ED. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), activated by LIPUS, contribute to the recovery of neurogenic ED. Furthermore, the survival and secretion function of Schwann cells are improved by LIPUS through activating tropomyosin receptor kinase B/protein kinase B/cyclic adenosine monophosphate-response element-binding protein (TrkB/Akt/CREB) pathway, thereby accelerating cavernous nerve repair. LIPUS is a safe and effective treatment modality for ED, which can restore the pathological changes in corpus cavernosum via multiple pathways. The long-term efficacy of LIPUS needs further investigation.

INTRODUCTION

Organic erectile dysfunction (ED), resulting from lesions in tissues or organs, is a multifactorial disorder involving the nervous system, hormones, vessels, and corpus cavernosum.1 Diabetes mellitus (DM), pelvic operation, hyperlipidemia, and other systemic diseases are major etiologies of ED.2 The underlying mechanisms of ED include endothelial dysfunction, neuropathy, cavernosal fibrosis, and apoptosis.3,4,5 Phosphodiesterase type 5 inhibitors (PDE5is) represent the first-line treatments for ED which could relax penile smooth muscle via the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway.6,7 However, nearly 30% of patients respond poorly to PDE5is.8 Furthermore, the short-term effectiveness and side effects of PDE5is also limited their clinical application.9 As an emerging alternative therapy, microenergy treatment has manifested promising therapeutic effect and safety owing to its non-invasive restorative capability.10,11

Shock wave is a mechanical wave that carries energy to the target organs, triggering a series of biological reactions.11,12 This technique can be applied across various diseases with adjustable energy settings. High-energy shock wave is primarily employed to disintegrate calculi, whereas low-intensity extracorporeal shock wave therapy (LIESWT) contributes to tissue repair and regeneration.13,14,15,16 LIESWT is the most widely used form of microenergy treatment in the field of andrology. LIESWT was first introduced for ED treatment by Vardi et al.,17 who performed LIESWT in 20 middle-aged men with vasculogenic ED, revealing its tolerability and efficacy. Numerous clinical studies have since demonstrated encouraging outcomes for LIESWT.18,19,20 LIESWT is currently recommended as an alternative therapy for ED by the European Association of Urology and the Asia Pacific Society for Sexual Medicine.21

As another form of microenergy treatment, low-intensity pulsed ultrasound (LIPUS) can produce biological effects similar to LIESWT.22 Ultrasound is an acoustic wave with a frequency above 20 000 Hz and has long been used for diagnostic imaging.23 The biological effects of LIPUS were first recognized in 1927, leading to its gradual adoption for therapeutic purposes.23 The microturbulence in intra- and intercellular fluids induced by ultrasound vibrations is the primary functional mechanism of LIPUS.22 Initially, LIPUS was predominantly used in rehabilitation medicine, where it could accelerate bone fracture healing and alleviate inflammation.24,25 The application of LIPUS in treating ED emerged later than that of LIESWT.23 Over the past decade, several studies have explored the treatment effect of LIPUS on organic ED.26,27,28,29,30,31 In a neurogenic ED animal model, LIPUS produced therapeutic outcomes comparable to those of LIESWT.32

However, LIPUS and LIESWT possess distinct physical properties. For instance, the thermal effect caused by LIPUS is minimal due to its extremely low intensity and pulsed output mode.33 LIPUS works primarily via micromechanical vibration and acoustic cavitation, whereas shock waves are instant high-pressure pulses with stronger mechanical stress and cavitation effects.34 LIPUS operates at an extremely low energy level (typically <3 W cm⁻²) and a relatively high frequency (0.7–3 MHz). In contrast, LIESWT is characterized by a low energy (0.1–0.3 mJ mm⁻²) and a low frequency (2–8 Hz).35 Therefore, the therapeutic mechanisms of these two microenergy modalities are likely not identical. It is well known that LIESWT improves erectile function via activating angiogenesis, recruiting progenitor cells, regenerating nerves, and improving microcirculation.36,37,38 However, the specific mechanism of LIPUS remains unclear due to limited research. Here, we reviewed the current evidence from basic research and clinical applications of LIPUS, aiming to verify its therapeutic effect on ED and elucidate the underlying mechanism.

A literature search was conducted using PubMed, Embase, ClinicalTrials.gov, and Web of Science, to retrieve all relevant articles published before February 28, 2025, without language restriction. The search strategy was as follows: (“low-intensity pulsed ultrasound” OR “LIPUS”) AND (“erectile dysfunction”). References of retrieved papers were also screened to identify additional publications. All original clinical and preclinical studies assessing the therapeutic effect of LIPUS for ED were included, while review articles, meta-analyses, case reports, and meeting abstracts were excluded. A comprehensive assessment of the efficacy and safety of LIPUS was performed based on clinical studies, while its underlying mechanism was explored using preclinical studies.

CLINICAL APPLICATION OF LIPUS

Although LIPUS has been used for connective tissue regeneration and neovascularization for years, its clinical application in ED only began 6 years ago.26,39,40 A total of seven relevant clinical trials were identified, and their key characteristics are summarized in Table 1. Among these studies, one specifically targeted diabetic ED, and another included patients with both ED and chronic prostatitis, while the remaining studies did not restrict the etiology of ED. Five of the studies are randomized controlled trials (RCTs), and two are retrospective analyses. All studies applied LIPUS at a frequency of 1.7 MHz, with treatment administered to four sites, namely the bilateral penile shafts and penile crura. However, differences exist in the energy intensity settings, which range from 0.2 W cm⁻² to 3 W cm⁻². Most studies delivered LIPUS treatment twice weekly for 4 consecutive weeks, with follow-up durations ranging from immediately after treatment to 3 months. The treatment regimens include LIPUS monotherapy and combination therapy together with PDE5is, herbal medicine, or pelvic floor therapy.

Table 1.

Characteristics of relevant clinical studies

Study	Sample size (n)	Type of ED	Grouping scheme	Setup parameter			Treatment protocol		Study design	Follow-up (month)	Mean change of IIEF-5 or IIEF-EF from baseline	Adverse event
				Energy intensity (W cm −2 )	Frequency (MHz)	Treatment site (n)	Sessions per week (n)	Treatment course (week)
Gao et al.27 2024	48	Severe ED	LIPUS + PDE5is vs LIPUS	0.2	1.7	4	2	4	Retrospective	1 and 3	7.8 vs 4.1	No
Li et al.28 2024	60	ED with chronic prostatitis	LIPUS + PDE5is vs PDE5is vs LIPUS	1.3 or 2.5	1 or 1.7	4	2	4	RCT	Posttreatment	6.5 vs 4.2 vs 3.2	No
Yang et al.30 2024	68	ED	LIPUS + pelvic floor therapy vs LIPUS	3	1.7	4	2	4	Retrospective	Posttreatment	6 vs 2.9	NA
Zhang et al.29 2023	137	ED	LIPUS + PDE5is + herb vs LIPUS + PDE5is	0.3	1.7	4	3	4	RCT	Posttreatment	6.3 vs 5.1	No
Chen et al.31 2022	323	Mild to moderate ED	LIPUS twice vs LIPUS thrice weekly	0.3	1.7	4	2 or 3	8 or 5	RCT	3	3.8 vs 3.2	No
Pei et al.45 2021	106	ED with diabetes	LIPUS + PDE5is vs PDE5is	NA	NA	4	2	8	RCT	Posttreatment	NA	NA
Cui et al.26 2019	103	Mild to moderate ED	LIPUS vs control	0.3	1.7	4	2	4	RCT	1, 2, and 3	4.1 vs 0.9	No

ED: erectile dysfunction; LIPUS: low-intensity pulsed ultrasound; PDE5is: phosphodiesterase 5 inhibitors; RCT: randomized controlled trial; IIEF-5: International Index of Erectile Function-5; IIEF-EF: International Index of Erectile Function-Erectile Function Domain; NA: not available

Cui et al.26 conducted a pioneering multicenter, randomized, double-blind, sham-controlled clinical study to evaluate the efficacy of LIPUS in treating mild-to-moderate ED. In this study, LIPUS was applied to each treatment site for 5 min. The treatment was administered twice weekly for 4 consecutive weeks, with an energy intensity of 0.3 W cm⁻², a frequency of 1.7 MHz, and a pulsed mode. There was a significant improvement in erectile function after LIPUS compared to the control group, with no adverse events reported.26 The positive response rate, defined as an increase of ≥2 points in the International Index of Erectile Function-5 (IIEF-5) score, was 67.50% and 20.00% in the treatment group and control group, respectively. Subsequent studies27,28,29,30,31 by other researchers adopted treatment protocols and setup parameters similar to those used by Cui et al.26 A study by Gao et al.27 investigated the therapeutic effect of LIPUS in patients with severe ED and revealed that the post-treatment IIEF-Erectile Function domain (IIEF-EF) score was significantly greater than baseline values. These findings implied that LIPUS was beneficial for patients with various severities of ED.

To enhance the therapeutic effect, some studies combined LIPUS with other therapies.27,28,29,30 Gao et al.27 found that LIPUS exhibited a synergistic effect with PDE5is in ED patients without comorbidities. The effective rate, defined as an increase in IIEF-EF score ≥7 points, was higher in the combined therapy group (66.67%) than that in the LIPUS-alone group (36.00%). Similarly, study by Li et al.28 indicated that the combination of LIPUS and tadalafil was more effective than LIPUS monotherapy, with response rates of 85% and 40%, respectively. Furthermore, Qingrezhuyu decoction, a traditional Chinese herbal medicine, could also enhance the effect of LIPUS.29 However, the addition of pelvic floor therapy with biofeedback electric stimulation did not produce extra benefits compared with LIPUS alone, with positive response rate of 81.6% and 76.7%, respectively.30

Patients typically received LIPUS treatment twice a week in most studies.26,27,28 To determine whether increasing the treatment frequency might enhance outcomes, Chen et al.31 compared twice-weekly and thrice-weekly protocols and found no significant difference between the two protocols, with positive response rates of 62.5% and 62.0%, respectively. This finding aligns with the results reported of a study on LIESWT, which indicated that patients benefited equally from treatment schedules of twice or thrice weekly.41 Therefore, increasing the number of treatments per week is not recommended.

Diabetic ED, defined as ED resulting from DM, is generally more severe and refractory compared to ED in non-diabetic populations.42 Numerous patients with diabetic ED responded poorly to PDE5is. Previous studies demonstrated that LIESWT successfully improved erectile function in diabetic patients.43,44 Only one study has examined the effect of LIPUS in diabetic ED to date, showing that LIPUS increased IIEF scores significantly.45 Neurogenic ED caused by cavernous nerve (CN) injury is also intractable with conventional therapies. However, the efficacy of LIPUS for neurogenic ED remains unclear due to the lack of relevant clinical studies.

A major limitation of current clinical trials is the short follow-up period, precluding definitive conclusions regarding the long-term efficacy of LIPUS. Therefore, studies with an extended follow-up duration are warranted in the future. Furthermore, the limited sample sizes and variability in LIPUS parameters across studies represent notable limitations. Only one study incorporated a sham treatment, revealing a minor placebo effect.26 Additional research with sham-controlled designs is required to strengthen the evidence. Since the application of LIPUS in ED is still in its early stage, more large-scale and high-quality RCTs are needed to further validate the clinical efficacy of LIPUS.

Collectively, the response rate of LIPUS, defined as achieving the minimal clinically important difference in IIEF-EF or IIEF-5 scores,46 ranged from 36.0% to 76.7% across the above-mentioned clinical studies.26,27,28,29,30,31 The available data suggest that LIPUS improves erectile function in patients with varying degrees of ED severity, and adjuvant therapies such as PDE5is can further enhance its efficacy. Thereby for patients responding poorly to monotherapy, a combination therapy with PDE5is might be a good choice. The optimal treatment frequency appears to be twice weekly, as more frequent sessions confer no additional benefit, whereas the superior parameter setting is unclear at present. Patients with diabetic ED respond positively to LIPUS treatment. However, whether other forms of ED, such as neurogenic ED, can benefit from LIPUS requires further investigation.

MECHANISM OF LIPUS IN DIABETIC ED

Before the initiation of clinical trials, several animal studies were conducted to investigate the efficacy and underlying mechanisms of LIPUS in ED. In this review, we summarize the biological mechanisms of LIPUS based on published preclinical studies, categorized by different ED models, including diabetic ED, neurogenic ED, and ED induced by cavernous injury. The findings from these preclinical studies provide a lower level of evidence compared with clinical research and are therefore primarily used to elucidate the molecular targets and signaling pathways of LIPUS rather than to direct clinical practice. Notably, insights obtained from animal studies on diabetic ED models have been validated in human studies. However, despite promising results in animal models, no clinical study has evaluated the effect of LIPUS in men with neurogenic ED.

LIPUS was first applied for the treatment of ED by Lei et al.,47 who investigated its therapeutic effect in rats with streptozotocin-induced type 1 diabetic ED. They found that LIPUS increased erectile function of rats and reversed several pathological alterations in the corpus cavernosum, such as an increase in the content of cavernous endothelium and smooth muscle, upregulation of the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), as well as amelioration of cavernosal fibrosis mediated by the transforming growth factor-β1/drosophila mothers against decapentaplegic protein/connective tissue growth factor (TGF-β1/Smad/CTGF) signaling pathway. Similarly, another study demonstrated that LIPUS elevated endothelial content in the penile tissue of type 1 diabetic rats, and this effect might be associated with the Piezo/extracellular-regulated protein kinase (ERK)/vascular endothelial growth factor (VEGF) pathway.48 Piezos are non-selective cationic mechanotransducers capable of converting mechanical stimuli into electrochemical signals and play essential roles in various physiological processes, such as touch sensation, baroreceptor reflex, and mechanical allodynia.49 A previous study demonstrated that Piezos were involved in LIPUS-induced proliferation of dental pulp stem cells,50 suggesting their importance as mediators of the biological effects elicited by LIPUS. Liu et al.48 found that LIPUS enhanced both the proliferation and secretion functions of adipose-derived stem cells (ADSCs), thereby improving their therapeutic effects in type 1 diabetic ED. Prohibiting Piezo or ERK in ADSCs abolished these LIPUS-induced beneficial effects.

Diabetes induces a high level of oxidative stress within the corpus cavernosum.51 Oxidative stress can impair mitochondrial function, leading to the production of excessive superoxide anion radicals and triggering a vicious cycle.52 Mitophagy, a mitochondria-specific form of autophagy, can mitigate oxidative stress by clearing abnormal mitochondria.53,54 To clarify the role of mitophagy in LIPUS-mediated protection for ED, Chen et al.55 established an in vitro diabetic model through treating corpus cavernosal endothelial cells (CCECs) with advanced glycation end products (AGEs). They found that LIPUS activated mitophagy by upregulating microtubule-associated protein 1 light chain 3 (LC3) and Parkin expression, therefore reducing mitochondrial reactive oxygen species (ROS) production induced by AGEs. Inhibiting mitophagy with 3-methyladenine abolished the protective effects of LIPUS on cell survival and tube formation, indicating that the therapeutic effect of LIPUS was closely related to mitophagy.

Due to the insufficient number of available studies, current findings only cover a restricted range of signaling pathways, and the roles of additional molecular mechanisms remain unclear. Moreover, previous animal studies have focused exclusively on type 1 diabetic models, leaving the potential efficacy of LIPUS in type 2 diabetic ED unverified.

These fundamental studies indicate that LIPUS improves type 1 diabetic ED via multiple mechanisms, such as upregulating eNOS and nNOS expression, inhibiting cavernosal fibrosis mediated by the TGF-β1/Smad/CTGF pathway, increasing smooth muscle and endothelial content, and ameliorating oxidative stress by inducing LC3- and Parkin-dependent mitophagy in CCECs (Figure 1). Moreover, LIPUS can enhance the proliferation and secretion functions of ADSCs by activating Piezo/ERK/VEGF pathway, which improves the therapeutic effect of ADSCs on ED.

Figure 1.

Mechanism of LIPUS in type 1 diabetic ED. LIPUS enhances angiogenesis, NO production, and smooth muscle and endothelium proliferation, while inhibiting fibrosis in penile tissues of rats with type 1 diabetic ED. LIPUS: low-intensity pulsed ultrasound; ED: erectile dysfunction; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; nNOS: neuronal nitric oxide synthase; TGF-β1: transforming growth factor-β1; Smad: drosophila mothers against decapentaplegic protein; CTGF: connective tissue growth factor; ROS: reactive oxygen species; CCECs: corpus cavernosal endothelial cells; ADSCs: adipose-derived stem cells; ERK: extracellular regulated protein kinase; VEGF: vascular endothelial growth factor.

MECHANISM OF LIPUS IN NEUROGENIC ED

Despite advancements in surgical techniques, the incidence of neurogenic ED caused by pelvic surgeries remains high.56 Novel alternative treatments were in urgent need because of the refractory nature of neurogenic ED to conventional pharmacological therapies.57 Several animal studies have examined the therapeutic effect and underlying mechanism of LIPUS on neurogenic ED.58,59,60 Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) possess synergistic transcriptional activity and can transduce mechanical signals in nucleus.58 A previous study demonstrated that LIESWT promoted recovery of injured sciatic nerves in rats via the YAP/TAZ pathway.61 Inspired by this finding, Liu et al.59 investigated whether LIPUS exerts its therapeutic effects through the same mechanism. They found that LIPUS upregulated the expression of YAP/TAZ and its downstream targets, including CTGF and cysteine-rich protein 61 (CYR61) in penile tissues, accompanied by alterations in fibrosis and smooth muscle content.

CTGF, a member of the cellular communication network factor family, participates in various biological processes, such as fibrosis and angiogenesis.62 Interestingly, the expression pattern of CTGF in the neurogenic ED model established by Liu et al.59 differed markedly from that in the type 1 diabetic ED model established by Lei et al.47 In rats with neurogenic ED, CTGF expression was lower than that in controls, and LIPUS treatment restored its levels.59 In contrast, CTGF expression was higher in rats with diabetic ED and was downregulated following LIPUS treatment. This discrepancy likely reflects intrinsic differences between the two ED models; however, further studies are warranted to clarify the underlying mechanisms.

CYR61 has been reported to phosphorylate eNOS via integrin, thereby increasing NO production in endothelial cells.63 However, the downstream targets of CTGF and CYR61 were not investigated by the authors. Conversely, they investigated the upstream signals of YAP/TAZ pathway and found that its activation was independent of both the classical Hippo pathway and the p38 mitogen-activated protein kinase (MAPK) pathway. The authors of this study speculated that other cellular signaling pathways mediated the LIPUS-induced YAP/TAZ activation.

Schwann cells (SCs) are the primary non-neuronal cells in peripheral nerves and can accelerate axonal regeneration through promoting cell proliferation and secreting neurotrophic factors.64 Therefore, the viability of SCs is essential for nerve repair. A recent study suggested that LIPUS enhanced the migration and proliferation of SCs isolated from CN and increased the expression of nerve growth factors.57 Simultaneously, the phosphorylation of tropomyosin receptor kinase B (TrkB), protein kinase B (Akt), and cyclic adenosine monophosphate-response element-binding protein (CREB) in SCs was elevated after LIPUS intervention. Since CREB functions as a transcriptional regulator with neuroprotective properties,60 these findings suggest a key role for the TrkB/Akt/CREB pathway. Consistent with this finding, in vivo experiments revealed that LIPUS promoted axonal regeneration after CN injury and improved erectile function, whereas inhibition of Akt or CREB reversed these effects.57

Another study investigated the role of SC-derived exosomes (SCs-Exo) in LIPUS-mediated nerve repair.65 It demonstrated that the axon elongation of major pelvic ganglion (MPG)/CN explants was enhanced by LIPUS-stimulated SCs-Exo, with better effects than non-stimulated SCs-Exo. In vivo, injection of LIPUS-stimulated SCs-Exo into the proximal CN of rats resulted in superior nerve regeneration and erectile function recovery. Transcriptome sequencing of MPG neurons detected several differentially expressed genes associated with axon regeneration, including phosphatidylinositol 3-kinase (PI3K), Akt, and forkhead box O (FoxO). FoxO represents a transcription factor regulated by the PI3K-Akt pathway, and plays a pivotal role in regulating metabolism and cell survival.66 Compared with unstimulated SCs-Exo, LIPUS-stimulated SCs-Exo significantly prompted the phosphorylation of PI3K, Akt, and FoxO.65 Inhibiting PI3K or Akt counteracted the axonal elongation induced by LIPUS-stimulated SCs-Exo. Authors of this study concluded that LIPUS modified the microRNA composition in SCs-Exo, thereby activating the PI3k-Akt-FoxO pathway in MPG and promoting nerve growth. Notably, several other studies have also reported the mediating effect of the PI3k-Akt-FoxO pathway in tissue regeneration triggered by nerve growth factors.67,68,69 Liu et al.32 found that LIPUS improved erectile function in rats with bilateral CN injury by ameliorating cavernosal fibrosis, although the underlying mechanism remains unknown.

These findings suggest that LIPUS activates YAP/TAZ and its downstream targets, including CTGF and CYR61 in corpus cavernosum, thereby alleviating neurogenic ED (Figure 2). Furthermore, LIPUS promotes the survival and secretion function of SCs through activating the TrkB/Akt/CREB pathway. SCs subsequently release numerous nerve growth factors and exosomes containing microRNAs to repair the injured CN by activating the PI3K-Akt-FoxO pathway in MPG. Previous studies have demonstrated that LIPUS improves SCs proliferation via glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/cyclin D1 pathway and promotes neurite outgrowth in PC12 cells through ERK1/2-CREB-Thioredoxin-1 signaling cascade.70,71 These cellular signaling pathways may participate in LIPUS-induced CN regeneration, although further investigations are required to define their exact roles.

Figure 2.

Mechanism of LIPUS in neurogenic ED. LIPUS promotes angiogenesis, smooth muscle proliferation, NO production, and nerve reparation, while inhibiting fibrosis in the penile tissues of rats with neurogenic ED. LIPUS: low-intensity pulsed ultrasound; ED: erectile dysfunction; NO: nitric oxide; YAP: yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif; CTGF: connective tissue growth factor; CYR61: cysteine-rich protein 61; TrkB: tropomyosin receptor kinase B; Akt: protein kinase B; CREB: cyclic adenosine monophosphate-response element-binding protein; NGF: nerve growth factor; Exo: exosome; PI3K: phosphatidylinositol 3-kinase; FoxO: forkhead box O.

MECHANISM OF LIPUS IN ED CAUSED BY CAVERNOSA INJURY

Lei et al.72 reported that LIPUS combined with bone marrow mesenchymal stem cells (BMSCs) improved erectile function in rats with cavernosa injury by downregulating insulin-like growth factor-binding protein 3 (IGFBP3), an exocrine protein that regulates the activity of insulin-like growth factor and modulates angiogenesis.73 Notably, the combined therapy produced superior outcomes compared with BMSCs alone. Moreover, in vitro experiments showed that LIPUS prompted the proliferation of BMSCs and reduced the expression of IGFBP3 in BMSCs.72 LIPUS-stimulated BMSCs exhibited a stronger ability to promote angiogenesis in umbilical vein endothelial cells, compared to untreated BMSCs. Inhibiting IGFBP3 with small interfering RNA could further accelerate tube formation in endothelial cells, suggesting the role of IGFBP3 in mediating the therapeutic effects of LIPUS.72

CONCLUSIONS

The major limitation of our review is the insufficient number of available studies, encompassing both preclinical and clinical research. Additionally, the follow-up duration in existing clinical studies did not exceed 3 months, leaving the long-term efficacy of LIPUS unclear. The heterogeneity of LIPUS parameters represents another notable limitation, precluding definitive conclusions about its therapeutic efficacy. Future studies should aim to identify the optimal treatment protocol for LIPUS. Moreover, animal studies investigating diabetic ED have exclusively used type 1 diabetic models, and the potential efficacy of LIPUS in type 2 diabetic rats remains to be determined. Therefore, further large-scale and high-quality RCTs are warranted to address these issues.

As a novel therapy for ED, LIPUS has attracted growing interest from researchers. Several studies have already been conducted to explore the efficacy of LIPUS, while others are currently ongoing or in the planning stage. Current evidence suggests that LIPUS can restore pathological alterations in the corpus cavernosum and enhance erectile function. Preliminary clinical studies have demonstrated that LIPUS improves erectile function across different severities of ED, and its therapeutic effect can be enhanced when combined with PDE5is. Basic research has shown that LIPUS can treat ED resulting from type 1 DM, CN injury, and cavernosa injury, via multiple signaling pathways. The underlying mechanisms involve upregulating eNOS and nNOS expression, increasing smooth muscle and endothelium content, inhibiting cavernosal fibrosis mediated by the TGF-β1/Smad/CTGF pathway, and ameliorating oxidative stress via LC3- and Parkin-dependent mitophagy in type 1 diabetic ED. YAP/TAZ activated by LIPUS contributes to the recovery of neurogenic ED. Furthermore, the survival and secretion function of SCs are improved by LIPUS through activating the TrkB/Akt/CREB pathway, thereby accelerating CN repair. Whether additional molecular pathways participate in LIPUS-induced improvement of erectile function remains an important topic for future investigation.

AUTHOR CONTRIBUTIONS

MLYW, JHL, and HL conceived the structure of the manuscript. WCX and TW conducted the literature search. MLYW and HL drafted the manuscript and created the figures. All authors read and approved the final manuscript.

COMPETING INTERESTS

The author JHL is a member of the Editorial Board of Asian Journal of Andrology, but he has not been involved in the peer-review or decision-making process for this manuscript. Other authors declare no competing interests.