Efficacy and Safety of Novel Low-Intensity Pulsed Ultrasound (LIPUS) in Treating Mild to Moderate Erectile Dysfunction

A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Study

Wanshou Cui; Huixi Li; Ruili Guan; Meng Li; Bicheng Yang; Zhanwei Xu; Maofan Lin; Long Tian; Xiaodong Zhang; Bao Li; Weiguang Liu; Zhilong Dong; Zhiping Wang; Tao Zheng; Weixing Zhang; Guiting Lin; Yinglu Guo; Zhongcheng Xin

Disclosures

Transl Androl Urol. 2019;8(4):307-319. 

In This Article

Abstract and Introduction

Abstract

Background: In our previous study, a novel low-intensity pulsed ultrasound (LIPUS) therapeutic device has been shown to improve erectile function non-invasively in a diabetic-induced erectile dysfunction (ED) animal model.

Methods: In order to investigate the efficacy and safety of LIPUS in the clinical treatment of patients with ED, a multicenter, randomized, double-blind, sham-treated, controlled clinical study was conducted at five medical centers, and 120 patients with mild to moderate ED were enrolled in the study. Patients were randomized into a sham-treated control group (40 patients) or a LIPUS-treated group (80 patients). LIPUS or sham treatment was applied to both sides of the penis shaft and crus for 5 min in each area, twice a week for four weeks. Assessment of efficacy and safety were evaluated using IIEF-5, Sexual Encounter Profile (SEP)-questionnaires 2/3, Global Assessment Question (GAQ), Erectile Hardness Score (EHS), Erection Quality Scale (EQS) score, and pain assessment [Visual Analogue Scale/Score (VAS)].

Results: Ten patients in LIPUS treatment group and 6 patients in sham treatment control group were excluded and the dropout rate is 13.33%. Response to treatment was identified as IIEF-5 score increased more than 2/3/4 points of post-treatment (12W) compared to pre-treatment (0W). The response rate in treatment group was 54/80 (67.50%), which was significantly higher than control group 8/40 (20.00%) at 12 weeks (FAS analysis). The percentage of patients with positive answers to SEP-3 (successful vaginal intercourse) were 58.97%, 64.1%, and 73.08% 4, 8, and 12 weeks after treatment which were significantly higher than 28.95%, 31.58%, and 28.95% respectively in control group (FAS, P<0.05). The positive responsive rates for GAQ in treatment group were about 2 to 3 times of that in control group (P<0.05). No treatment-related adverse events (AEs) were found, including local petechia or ecchymosis and hematuria.

Conclusions: Current study indicates that LIPUS can safely and effectively treat patients with mild to moderate ED without significant AEs, which is related to the mechanical force of LIPUS and can restore the pathological changes of the corpus cavernosum. LIPUS is a promising alternative treatment for ED treatment in the near future, while further research is remanded.

Introduction

Erectile function requires coordinated interaction of multiple organ systems include psychological, endocrine, vascular, neurologic regulation. Erectile dysfunction (ED) is a common disease, which affects more than 50% of men between the ages of 40 and 70 years.[1] In 2010, a report from the European Male Ageing Study (EMAS) has illustrated that one third of men (prevalence of 30–64%) in their population were dissatisfied with their overall erectile function or sexual relationship.[2] Studies indicated that more than 50% ED showed organic causes due to cardiovascular disease, diabetes mellitus, trauma or surgery on colon, bladder, prostate, genitourinary, neurologic causes (lumbar disc, MS, CVA), Priapism, hormone deficiency et al., which could induce corpus cavernosum pathological changes include corpus cavernosm smooth muscle apoptosis and fibrosis, endothelial dysfunction neuropathy et al.

Currently, the first line ED therapeutic approach is phosphodiesterase type 5 inhibitors (PDE5is). And the second line choices include intracavernosal injection therapy, vacuum devices used for treating mild to moderate ED patients once a time symptom treatment, and the first line and second line therapies no responder severs ED patients need to be treated by penile prostheses implantation surgery.[3,4] The most obvious limitation of all these above-mentioned therapies is symptomatic treatment and could not restore the pathological changes in erectile tissue significantly.

Although some of alternative therapies for ED have been extensively reported recently, including exogenous stem cell therapy, gene therapy, and tissue engineering et al. in preclinical studies, however, there is still needed long-term investigation before real clinical approach due to ethic, immunological problem, limited efficacy and safety problems.[5–9] Very recently, low energy shock wave therapy (LESWT), a form of physical therapy in micro-energy therapy, was shown to significantly improve erectile function both in animal studies and clinical settings.[9,10]

A micro-energy related therapy for the management of ED represents a typical model of convergence science of life science, physical sciences, and engineering. Another important form of energy medicine in the field of translational medicine is low-intensity ultrasound. Ultrasound with acoustic frequencies in excess of 20,000 Hz has traditionally been used in imaging medicine. However, since 1927, its biological effects have also been extensively explored.[11] Low-intensity pulsed ultrasound (LIPUS) is a form of pulse ultrasound that is delivered at an intensity lower than 3 W/cm2. The energy is delivered in a pulsed fashion to reduce the thermal effect of ultrasound that might induce local tissue damage. Previous studies have demonstrated that LIPUS has beneficial effects for connective tissue regeneration, inflammation control, and neovascularization.[12–16]

The novel device of LIPUS therapy device for ED was developed by Beijing Wanbeili Medical Instrument Co., Ltd., and cooperated with the Molecular Biology Laboratory, Andrology Center of Peking University First Hospital, and the Knuppe Molecular Urology Laboratory of University of California, San Francisco. The novel ultrasound pulse duration - pulse interval ratio is 1:4 (200 μs:800 μs) at 1,000 Hz and frequency of 1.7 MHz. In our previous study, this LIPUS therapy improved the pathological changes in penile erectile tissue of streptozotocin (STZ)-induced diabetic rats and enhanced erectile function [intracavernous pressure (ICP)], increased endothelial and smooth muscle content, increased expression of eNOS and nNOS, and decreased collagen and fiber changes with down-regulation of TGF-β1/Smad/CTGF signaling pathway. No treatment-related adverse events (AEs) were found in animal studies.[9]

In order to investigate the efficacy and safety of LIPUS in the clinical treatment of patients with ED, a multicenter, randomized, double-blind, sham-treated, controlled clinical study was conducted.

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