Erectile dysfunction associated with prostate cancer treatment and therapeutic advances: a narrative review

Introduction

According to the World Health Organization, prostate cancer (PCa) is the most common type of cancer in 118 countries/regions (as of 2022) and the second most common malignant tumor in men worldwide (1,2). In 2020 alone, there were 1,466,680 new cases, accounting for 7.3% of the total new cancer cases, which led to 396,792 deaths, constituting 4.1% of the total cancer-related deaths. It is projected that by 2040, the number of new annual PCa cases worldwide will increase to about 2.3 million, with number of related deaths reaching 740,000 (3). The treatment of PCa not only poses a threat to health but also may lead to side effects such as erectile dysfunction (ED), even when accounting for the shared risk factors between PCa and ED, including aging, obesity, metabolic disorders, and sleep apnea (4,5). ED is defined as the inability to achieve and maintain an erection sufficient for satisfactory sexual activity, either occasionally or consistently (6). Higher residual radiation doses in the penile bulb and penile root after radiation therapy (RT) (7), damage to the neurovascular bundles of the prostate due to radical prostatectomy (RP) (8) and cryotherapy (9), and reduced testosterone levels due to androgen deprivation therapy (ADT) (10) can all lead to ED. With the advancement of diagnostic and therapeutic equipment and technology, the relationship between PCa treatment and ED is undergoing transformation. Emerging physical energy therapies (11), the rise of precision medicine (gene and targeted therapies) (12), the exploration of biotissue engineering and nerve transplantation (13), and research on traditional Chinese medicine (TCM) (14) in the treatment of ED represent new approaches for addressing ED in patients with PCa. Therefore, it is essential to systematically review the connection between PCa treatment and ED and to discuss the latest strategies for managing ED. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-514/rc).

Methods

This study employed a systematic literature search strategy to ensure comprehensiveness and accuracy (Table 1). We established the following inclusion criteria: (I) all studies must be directly related to the treatment of PCa and its impact on ED, including the latest advancements in the treatment of ED; (II) studies must be published in peer-reviewed academic journals to ensure the quality of the research; (III) we limited the language of the studies to English to ensure our accurate understanding and analysis of the literature. Exclusion criteria included: (I) non-empirical studies (such as case reports); (II) studies with duplicate data publication; (III) those with small sample sizes that might affect the generalizability of the results. Through these criteria, we systematically screened relevant literature from databases such as PubMed, Excerpta Medica, Web of Science, Scopus, and the Cochrane Library from June 1966 to June 2024. By employing this method, we were able to conduct a narrative review of the evolution of PCa treatment methods, with particular emphasis on the incidence of ED as a complication of treatment. Furthermore, we summarized the latest treatment methods in the field of ED, providing valuable references for clinicians and researchers.

Discussion

The impact of PCa treatment on erectile function (EF)

Active surveillance (AS) and ED

The widespread use of prostate-specific antigen (PSA) screening and improved biopsy techniques have increased the early diagnosis rate of PCa by 10% to 80% globally (15). A study has shown that the metastasis and mortality rates of early-stage, localized PCa are extremely low within 10 to 15 years (16). This indicates an urgent need to explore new treatment plans for patients with early, low-risk, localized PCa to avoid the decline in quality of life caused by overtreatment. AS is a method of assessing tumor progression by monitoring PSA via digital rectal examination and imaging, enabling the adjustment of the treatment plan in a timely manner (17). A prospective study by Newcomb et al. published in JAMA showed that 49% of patients undergoing AS had no progression or treatment within 10 years, with a metastatic cancer incidence rate of less than 2% and a cancer-related mortality rate of less than 1% (18). A multicenter study involving 5,302 patients by Bokhorst et al. also produced similar results, with a 10-year distant metastasis rate and cancer-specific mortality rate of just 0.5% and 0.1%, respectively (19). A prospective study by Hirama et al. assessing the impact of AS on 525 patients with PCa showed that the patients had a good quality of life and mental health status, with low levels of anxiety and depression (20). These results confirm that AS is an effective management strategy for early-stage, localized PCa. In developed countries, 37.9% to 74% of patients with PCa select AS as their first choice (21-23).

Compared with active treatment, AS significantly reduces the incidence of ED in patients with PCa. A cohort study by Donovan et al. showed that among patients with PCa undergoing AS, 52% at 6 months, 41% at 36 months, and 30% at 6 years were able to maintain an erection sufficient for sexual intercourse, representing superior outcomes to those of patients undergoing RP or RT at these time points (24). Alberti et al. reviewed 17 prospective clinical experiments using different patient-reported outcome tools [such as Expanded Prostate Cancer Index Composite 26 (EPIC-26)], including two randomized controlled trials (RCTs) and other prospective observational or cross-sectional studies, and found that the impact of AS on EF was minimal compared to that of RP and RT (25).

It has been reported that PSA biopsies may increase the risk of ED. A longitudinal study by Fujita et al. followed 333 patients with PCa undergoing AS, of whom 69% completed follow-up. Those who underwent 3 or more biopsies had an average decrease of 5.7 points in their Sexual Health Inventory for Men (SHIM) score, while those who underwent 0 to 2 biopsies had an average decrease of 2.3 points (26). However, the observational study by Braun et al. (27) and Pearce et al. (28) did not find a direct link between the number of biopsies and ED. The application of different prostate biopsy techniques significantly influences the risk of ED. Extensive research indicates a marked decrease in the International Index of Erectile Function-5 (IIEF-5) scores at 1, 3, and 6 months post transrectal prostate biopsy (TRPBx) (29-32). Transperineal prostate biopsy (TPB) is favored by clinicians due to its more effective sampling of the anterior and apical regions of the PCa. The largest study examining ED following TPB included 610 patients who underwent 18-core (extended TPB), 360 who underwent 28-core (saturated TPB), and 210 who underwent 32-core biopsies. The findings revealed mild ED in 15 (4.2%) of the extended TPB group, 7 (6.4%) of the saturated TPB group, and 7 (7%) of the saturated TPB group one month after biopsy, with no persistent effects observed after three months. Additionally, a study by Chong et al. found a significant decrease in IIEF-5 scores one month post-biopsy in 64 patients who underwent TPB (19.5 vs. 10.5) (P<0.001) (33). However, a single-center, observational, prospective study by García Rojo et al. noted no significant difference in IIEF-5 scores at 3- and 6-month post-biopsy compared to pre-biopsy levels following both transrectal and transperineal prostate biopsies (34). These differences may be attributed to the location of the tumor, the skill level of the clinician performing the biopsy, and the patient’s own condition. The progression of PCa can lead to an increase in prostate volume, which in turn can cause lower urinary tract symptoms (LUTS), which have been confirmed to be an independent risk factor for ED (35,36). In the future, incorporating patient preferences and quality of life assessments into the standards of AS plans can aid in comprehensively monitoring patients’ EF and effectively improving their quality of life. However, it is important to note that unhealthy lifestyle habits such as smoking, and obesity may simultaneously cause increases in PSA levels and ED, indicating that these factors should be considered when establishing AS criteria (37,38).

RT and ED

RT, including external beam radiation therapy (EBRT) and brachytherapy (BT), is an effective treatment for PCa. Before external beam RT is implemented, it is necessary to delineate the radiation target area. The resolution of early two-dimensional X-ray technology and limitations in three dimensions made it difficult to accurately locate the RT target area. In addition, previous three-dimensional conformal radiation therapy (3DCRT) relied on fixed beams and collimators to block the rays, causing damage to surrounding tissues and precipitating complications such as ED and urinary incontinence. Several prospective trials have shown that the incidence of ED after 3DCRT ranges from 7% to 72% (39-44). Subsequently, the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) have significantly improved the accuracy of delineation, with CT reducing the target error by more than 30% (45) and MRI being 30% more accurate than CT (46,47).

In the 1990s, intensity-modulated radiation therapy (IMRT) gradually became the preferred strategy of clinicians. IMRT involves the adjustment the collimator from different angles to irradiate the tumor through computer control and imaging guidance, providing a higher radiation concentration and reducing the incidence of ED. Brown et al. followed up with 32 patients who underwent IMRT, and in a median follow-up time of 36.8 months, 50% of patients reported a SHIM score of less than 10 (48).

Hypofractionated RT, which rose to favor in the beginning of the 21st century, utilizes the repair ability of healthy cells and the insufficient repair of tumor cells and administers precise doses in fractions to eliminate the tumor and protect normal tissues. Stereotactic body radiation therapy (SBRT) represents a refinement of this method, enhancing the accuracy and efficiency of hypofractionated RT through three-dimensional precise positioning, further reducing the incidence of ED. In a single-center prospective study, among 184 patients with initially intact EF who underwent SBRT treatment, the functional erection preservation rate was 57% at 24 months and decreased to 45% at 60 months (49).

In recent years, image-guided radiation therapy (IGRT) has provided real-time monitoring of tumors and surrounding tissues by employing CT and MRI during treatment, allowing for the precise positioning and dynamic adjustment of treatment plans. From the IGRT substudy of the CHHiP (Conventional or Hypofractionated High-Dose Intensity-Modulated Radiotherapy for Prostate Cancer) trial, Murray et al. found that IGRT technology reduced the radiation dose to the penile bulb, reducing the risk of severe ED in patients with PCa (50).

At the beginning of the 21st century, BT became increasingly popular due to its lower incidence of ED. This method acts directly on the tumor by implanting radioactive particles or isotope catheters. Incrocci et al.’s study showed that BT with iodine-125 (I-125) or palladium-103 (Pd-103), whether used alone or in combination, yielded an ED incidence rate between 5% and 51% (51). The latest RT technology uses the “Bragg peak” effect of heavy particles, such as protons and carbon ions, which release a maximum amount of energy before penetrating and stopping at the tumor tissue, thereby effectively destroying tumor cells while minimizing the impact on surrounding healthy tissues. Ho et al. followed up with 254 patients who received proton therapy for as long as 7.1 years, finding that their EF baseline of 90% decreased to 62% after 1 year and to 67% after 5 years (52). The peak of ED occurs between 6 months and 2 years after RT (53,54).

It is currently believed that the etiology of ED caused by RT primarily revolves around the radiation-induced damage to penile vasculature, cavernous nerves, and penile tissue. In the 1980s, Goldstein et al. performed selective internal pudendal artery angiography on patients who had undergone RT, revealing obstructive vascular disease within the pelvic radiation field (55). In 1998, Zelefsky and Eid applied ultrasound scanning of cavernous tissue in patients treated with RT and discovered that arterial dysfunction is a principal cause of ED after RT. Subsequent animal studies have revealed that the reduction of nitric oxide synthase (NOS)-containing nerve fibers within the penile corpora may play a critical role in the development of ED following RT (56), a finding that could provide significant insights into understanding the pathogenesis of post-RT ED (57). Furthermore, the incidence of ED is also correlated with patient age, economic status, and the standard of local healthcare (58,59).

The development of RT technology has consistently relied upon improving the accuracy of delineation and creating more effective drug administration methods. In the future, cutting-edge imaging technology—such as use of specific biomarkers—intraoperative real-time monitoring of IGRT, and the development of safer and more effective radiation sources required for BT, will advance RT strategies and reduce the occurrence of ED.

Cryotherapy and ED

In 1966, Cooper and Hirose pioneered the first generation of modern cryotherapy using liquid nitrogen cooling probes (60). In 1968, Soanes and Hirose applied this technology to the ablation of prostate tumors, but due to the lack of real-time monitoring and protection of surrounding tissues, thus often led to complications such as urethral rectal fistula (61). Unfortunately, few studies have explored the impact of cryotherapy on EF. In 1993, Onik et al. conducted a study introducing ultrasound imaging monitoring technology into cryotherapy, and the results showed that 65% of the 14 patients with normal preoperative EF experienced ED (62).

In the 1990s, an innovative cryotherapy device leveraging the Joule-Thomson throttling refrigeration principle was developed, enabling rapid cooling for cryotherapy treatment with argon gas and controlled needle removal through heating with helium gas. Unexpectedly, related studies on the impact of the third-generation cryotherapy on EF produced highly discrepant findings. In Asterling et al.’s prospective study, 20 out of 25 patients (80%) with normal preoperative EF experienced ED during the follow-up period of 3 to 54 months after surgery (63). Zhou et al.’s meta-analysis also found that patients had a higher incidence of ED after cryotherapy (64). However, in Roberts et al.’s retrospective study, only 20.1% of the 380 patients who underwent cryotherapy reported ED after 12 months (65). This difference may be related to the patient’s age, physical condition, cancer staging, and tumor location. The mechanism of ED caused by cryotherapy is related to the cryogenic damage to the neurovascular bundle near the prostate (9). In the future, cryotherapy can employ imaging and tumor cell markers to achieve precise positioning of the treatment area, which is expected to further reduce the damage to the neurovascular bundle and more effectively preserve patients’ EF.

RP and ED

RP often leads to cavernous nerve damage due to intraoperative traction, thermal injury, postoperative local tissue inflammation, and ischemia, which in turn triggers a series of pathological changes such as apoptosis, pyroptosis, and autophagy of smooth muscle cells, ultimately resulting in the onset of ED (Figure 1).

Figure 1 Causes of erectile dysfunction after radical prostatectomy. RP, radical prostatectomy; CC, corpus cavernosum; CCSMC, corpus cavernosum smooth muscle cell; ROS, reactive oxygen species; ED, erectile dysfunction.

In 1905, Young was the first to use the perineal approach for radical perineal prostatectomy (RPP) (66). In 1945, Millin described retroperitoneal prostatectomy, laying the foundation for the later retropubic radical prostatectomy (RRP) (67). Walsh first used this approach for RRP in 1949. However, almost all patients experienced severe ED (68). Subsequently, research into RP has long sought the means to reducing RP-related ED complications.

In 1983, Walsh discovered the neurovascular bundle that runs along the posterolateral aspect of the prostate through autopsy, and then developed an RRP technique that retains these neurovascular bundles. That is, by making an incision in front of the neurovascular bundle and closely separating from the prostate, to reduce the damage to the cavernous nerves (69). Walsh et al. modified nerve-sparing surgery on 12 patients with PCa aged 44 to 68 years, and all patients were able to have erections 8 weeks after surgery, with 50% successfully achieving vaginal penetration and orgasm (69). Biopsy of the prostate specimen after the modified operation showed that the technique could more thoroughly remove the tumor due to it being performed completely within the lateral pelvic fascia (69,70). Subsequently, the nerve-sparing RP technique was widely used in the clinic, effectively improving the EF of patients after RP.

In the 1990s, significant developments were made in laparoscopic radical prostatectomy (LRP) technology (71). However, due to its high technical requirements, it was not until Binder and Kramer introduced the da Vinci robot in 2000 that robot-assisted laparoscopic radical prostatectomy (RALP) began to be widely adopted (72). Subsequently, Menon et al. optimized the RALP technique and proposed an improved retropubic approach, the Vattikuti Institute prostatectomy technique, to better protect the neurovascular bundle and lateral prostate fascia, making RALP the mainstream method of surgical treatment for PCa in the United States (73).

Data from Memorial Sloan Kettering Cancer Center showed that from 2008 to 2015, the proportion of patients undergoing RALP increased from 21% to 68%, while the proportion of patients undergoing open radical prostatectomy (ORP) and LRP decreased from 29% and 50% to 14% and 28%, respectively (74). In Moretti et al.’s meta-analysis, at 6 months after surgery, the recovery rate of EF in patients undergoing RRP, LRP, and RALP was 30%, 44%, and 54%, respectively; 18 months later, the recovery rate increased to 58%, 52%, and 67%, respectively, with the recovery rate of RALP consistently being the highest (75). Yang et al. (76) conducted a study assessing the efficacy of transvesical robot-assisted RP in treating localized PCa. They found that the approach, which involves a combined longitudinal incision through the bladder neck and prostate, not only effectively removes the tumor but also particularly preserves the anatomical structures related to sexual function and urinary control, which is especially beneficial for the recovery of EF postoperatively. In 2023, Zhang et al. proposed a modified Retzius space preservation technique (Hood technique) for the anterior approach. This method only requires limited dissection of the fat layer on the surface of the bladder’s anterior aspect in establishing a surgical operating space and maximizes the preservation of the key anatomical structures around the urethra related to urination and EF. However, there is a lack of large clinical trials conducted on the impact of this technique on EF (77). It is worth noting that there is an association between single-port or multi-port robot-assisted laparoscopic surgery and the incidence of postoperative ED, but regrettably, there are currently no clinical data reported on this matter.

Intraoperative cavernous nerve monitoring is crucial for protecting EF. Electrical nerve stimulation, as the earliest intraoperative nerve monitoring technology, is widely applied via the CaverMap device, but faces limitations in clinical application due to insufficient specificity and a high false-positive rate (78,79). Optical coherence tomography (OCT) is an imaging technology based on fiber optics, which can be integrated into surgical instruments and achieve real-time high-resolution tissue imaging through backscattered light (80,81). Experimental versions of this technology in RP are being explored. Other intraoperative nerve monitoring technologies such as optical nerve stimulation (ONS), fluorescence dye marking, confocal, and multiphoton microscopy have not been widely adopted due to their distinct limitations (82-84).

The future development of RP surgery needs to continue in the direction of reducing damage to the prostatic neurovascular bundles, such as developing more real-time and convenient intraoperative neural imaging technologies, and improving computer-assisted robotic surgery to reduce intraoperative injuries. In addition, strengthening the rehabilitation of patients’ postoperative EF is also crucial.

Immunotherapy and ED

In 2000, Hurwitz found that anti-CTLA-4 (a T-cell inhibitory receptor) treatment could reduce the grade of prostate tumors in mice, although this treatment was accompanied by prostatitis and destruction of epithelial cells (85). This finding suggests that PCa cells may express specific antigens and may be suitable for immunotherapy. A phase III trial of sipuleucel-T, a customized vaccine based on modified immune cells from the patient, was conducted in 2006 involving 127 patients from 19 clinical centers. Patients treated with sipuleucel-T had a median overall survival of 25.9 months, while patients treated with placebo had a median overall survival of 21.4 months (86). In 2010, the US Food and Drug Administration (FDA) approved sipuleucel-T for the treatment of metastatic castration-resistant prostate cancer (mCRPC), marking the beginning of immunotherapy for this disease (87). There are currently several immunotherapy drugs being studied, including CTLA-4 inhibitors, PD-1/PD-L1 inhibitors, and antibody therapies targeting prostate-specific membrane antigen (PSMA). However, their efficacy is limited, and their side effects are severe (88-90).

There are currently no reports of PCa immunotherapy causing ED. Ryder et al.’s analysis showed that among 211 melanoma patients treated with ipilimumab, 8% developed pituitary inflammation, and 6% developed hypothyroidism or thyroiditis, all of which increased the risk of ED (91). Similarly, Mahzari et al.’s study found that among 6 patients who developed pituitary inflammation after treatment with Ipilimumab, 4 (67%) had central hypogonadism (92). These cases of ED were not directly caused by immunotherapy, and the patients did not have PCa. Additional large-sample, double-blind, clinical RCTs are needed in the future to clarify the connection between PCa immunotherapy drugs and ED.

Chemotherapy and ED

Early chemotherapy for PCa relied on nonspecific cytotoxic drugs such as estramustine, which could alleviate symptoms but demonstrated limited ability in improving survival rates (93). Subsequently, it was found that the combination of anthracycline drugs such as mitoxantrone and prednisone could alleviate pain and improve the quality of life, but it also failed to significantly extend the patient’s survival period. In 2004, the US FDA approved docetaxel for the treatment of mCRPC, marking an important milestone in PCa chemotherapy (94,95). Tannock et al.’s phase III clinical trial showed that compared with mitoxantrone plus prednisone, docetaxel combined with prednisone performed better in extending the survival period of patients with advanced hormone-resistant PCa, relieving pain and reducing PSA levels (96). Unfortunately, almost all patients developed drug resistance within 6–8 months (97). To solve this problem, cabazitaxel (CAB), a second-generation semisynthetic taxane drug, was introduced for the treatment of patients with mCRPC who failed docetaxel therapy. In 2010, de Bono et al. conducted the TROPIC phase III clinical trial, which showed that cabazitaxel could effectively reduce the risk of PCa-related death, but hematological adverse events (neutropenia, leukopenia, and anemia) were also more common (98). In recent years, the combination of platinum drugs (such as carboplatin and cisplatin) and taxane drugs has shown potential. The literature review by Leal and García-Perdomo indicated that the clinical overall response rate and the PSA response rate for combination chemotherapy involving platinum and paclitaxel ranges from 23% to 78% and from 17% to 100%, respectively (99).

Kataoka et al.’s animal experiments showed that after 4 weeks of docetaxel treatment, the testosterone levels in the experimental group rats decreased; moreover, the ratio of intracranial pressure to mean arterial pressure (ICP/MAP) in the experimental group was significantly lower than that in the control group, indicating that docetaxel has the potential to induce ED (100). Unfortunately, there is currently no clear clinical evidence confirming that chemotherapy induces ED. A multicenter study involving 428 patients with PCa showed that 48% of patients experienced gonadal dysfunction when taking oral anticancer drugs (such as platinum and paclitaxel) (101). This suggests that chemotherapy drugs may indirectly affect EF by causing gonadal dysfunction. In addition, it was found that docetaxel may cause peripheral neuropathy, which may further lead to ED (102,103). Psychological problems such as anxiety and depression caused by chemotherapy, as well as side effects such as fatigue, may also degrade the overall health status of patients, indirectly leading to ED. More research directly investigating the impact of chemotherapy drugs on ED is required.

ADT and ED

In 1941, Huggins and Hodges first discovered the benefits of castration and estrogen injection for metastatic PCa, laying the foundation for ADT (104). Subsequently, gonadotropin-releasing hormone agonists (GnRH-As) became the mainstream drugs for ADT in the 1980s (105). Studies have shown that the overall survival rate of GnRH-A is comparable to that of orchiectomy (106). However, GnRH-As may initially cause a surge in testosterone, leading to disease progression. To prevent this reaction, Kuhn et al. used a combination of nilutamide and buserelin, significantly alleviating the symptoms caused by the surge in testosterone (107). In addition, gonadotropin-releasing hormone antagonists (GnRHs) represent an alternative choice for preventing the surge in testosterone and are superior to GnRH-A in terms of PSA progression and overall survival rate. However, almost all drug treatments will eventually lead to mCRPC, and thus androgen receptor antagonists are being increasingly favored in clinical treatment. The benefit of abiraterone in the treatment of castration-resistant PCa was confirmed in Ryan et al.’s multicenter, randomized, double-blind phase III clinical trial (108), which found that the median overall survival of the abiraterone combination group was 34.7 months, while the placebo group’s survival was 30.3 months; additionally, the radiographic progression-free survival was 16.5 and 8.3 months, respectively (109). Currently, androgen receptor antagonists are often used in combination with ADT, with the aim of more effectively inhibiting the growth of PCa by simultaneously reducing androgen levels and blocking its receptors. Emerging treatment strategies include biphasic androgen therapy (BAT) and rapid androgen testosterone cycling (RAC). BAT attempts to induce the periodic apoptosis of cancer cells by cycling between low androgen levels and high androgen levels. Meanwhile, RAC is a more aggressive method, involving more frequent changes in androgen levels, with the purpose of interfering with the adaptability and survival of cancer cells through rapid changes in hormone levels. However, there is currently a lack of extensive clinical trials evaluating the effectiveness of BAT and RAC in the treatment of PCa. Only Teply et al. reported that among 21 asymptomatic metastatic patients with CRPC who progressed after enzalutamide treatment, 15 had a 50% decrease in PSA levels after BAT treatment (110).

However, regardless of the improvements made to ADT, ED remains an inevitable complication. Gryzinski et al. reviewed the previous ADT literature and found that ADT increased the risk of ED by threefold (10). The reason lies for this is that testosterone is essential for maintaining normal EF, and low levels of testosterone cause vascular endothelial dysfunction and reduce penile blood flow, nitric oxide levels, and the enlargement of phosphodiesterase type 5, thereby affecting the quality and duration of erections (111). Exogenous testosterone supplementation may alleviate ED but is contraindicatory to ADT and may promote tumor development (112,113). In the future, ADT may incorporate the assessment of patients’ EF into its protocols, allowing for timely intervention in cases of ED caused by treatment.

Emerging treatment strategies for ED

Traditional treatment methods for ED include psychosocial intervention, phosphodiesterase type 5 inhibitors (PDE-5is), intracavernous injection of alprostadil, vacuum erection devices (VEDs), testosterone replacement therapy, and prosthesis implantation, but each of these methods has limitations and complications. For patients with organic lesions, the efficacy of psychosocial intervention therapy is poor. PDE-5is are only effective in 35% of ED patients, and their use in combination with nitrates or alpha-blockers can lead to hypotension (114-116). Intracavernous injection and VED are associated with poor patient compliance and a series of complications. The controversy surrounding testosterone replacement therapy is primarily centered on whether exogenous testosterone increases the risk of tumor progression or recurrence (117,118). Penile prosthesis implantation also involves complications such as mechanical failure, infection, penile perforation, and cross-infection (119,120). Therefore, more efficient and safer treatment plans urgently need to be developed.

Physical energy therapy

Physical energy, which can promote angiogenesis and reduce inflammatory responses, has been widely used in the treatment of ED (121). Extensive RCTs and prospective clinical studies have validated that low-intensity extracorporeal shock wave therapy (LI-ESWT) significantly improves the IIEF-5 scores in patients with ED (122,123). A systematic review and meta-analysis conducted by Clavijo et al., encompassing 7 studies and 602 subjects, revealed a significant finding: compared to those receiving sham therapy, males undergoing LI-ESWT demonstrated a statistically significant change in the International Index of Erectile Function-Erectile Function (IIEF-EF) scores from baseline to follow-up (124). A number of recent studies have shown that LI-ESWT can be effective in treating ED after RP and ED caused by RT for PCa. Examining the literature on patients with ED after RP and treated with LI-ESWT, Rho et al. found that the International Index of Erectile Function (IIEF) scores increased significantly after 3 or 4 months of LI-ESWT (125). In a study by Chan et al., LI-ESWT was used to treat patients with ED after RP for PCa, and the results showed that the IIEF-5 scores of patients increased from 10 to 19 (126). Lu et al.’s study demonstrated that, compared to monotherapy with tadalafil, the combination of LI-ESWT and tadalafil significantly improved patients’ IIEF-5 scores after 1 month (15.34±7.15 vs. 13.96±7.71, P=0.039) (127). In the treatment of ED after RP, low-intensity pulsed ultrasound (LIPUS) has been widely used since it is a noninvasive, low-energy method. Cui et al.’s RCT showed that LIPUS treatment for 12 weeks can significantly improve the IIEF-5 scores of patients with mild-to-moderate ED (128). According to research on animals, LIPUS can increase the amount of smooth muscle cells, stimulate the growth of Schwann cells, encourage peripheral nerve regeneration, and increase the expression of neuronal nitric oxide synthase (nNOS) in the cavernous and dorsal penile nerves, the expression of neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and ICP (129-133). A substantial body of research currently indicates that the combination of LIPUS with tadalafil therapy is more effective in improving EF than the use of PDE-5 inhibitors alone (134,135). Pulsed electromagnetic field stimulation therapy (PEMST) is another simple, noninvasive method. The Rainer team conducted a double-blind, placebo-controlled trial to evaluate the efficacy of PEMST on ED. Twenty patients with ED or orgasmic disorder were subjected to 10 minutes of PEMST at an intensity of 40% and a frequency of 20 Hz. The results demonstrated a significant improvement in EF following the therapy (136). Physical energy therapy methods have demonstrated significant potential in animal and clinical trials, providing effective and side effect-free options for the treatment of ED. However, current research is often constrained by small sample sizes, which limit the broad applicability of the results. The varying responses to treatment effects among different patients necessitate personalized assessments prior to therapy. There is an urgent need for large-scale clinical trials in the future to delve deeper into the impact of physical energy therapy on ED.

Penile tissue engineering and nerve transplantation therapy

An interdisciplinary field of study, tissue engineering combines biomedical engineering, cell biology, material science, and biotechnology to solve medical problems by building, repairing, or replacing damaged tissue. In the application of ED treatment, tissue engineering mainly involves the printing and implantation of artificial penile scaffolds. Kershen et al. implanted cultured human penile corpus cavernosum smooth muscle cells (CCSMCs) on degradable polyethylene glycol acid polymer scaffolds and then implanted the scaffolds into the penile corpus cavernosum, observing that the implants contributed to the formation of tissue blood vessels (137). Ji et al. inoculated purified muscle-derived stem cells (MDSCs) on decellularized penile corpus cavernosum collagen matrix (ACCM) and implanted them into the rabbit peritoneum. They found that through immunohistochemistry, scanning electron microscopy, and other means that MSCs can effectively increase the content of alpha smooth muscle actin (α-SMA) and NOS-positive cells in the penis (13). Future research will focus on optimizing the selection of cells and scaffold materials, enhancing the biocompatibility and functional integration of implants, and further conducting human trials, which may provide better therapeutic outcomes for patients with ED.

Nerve transplantation has shown significant potential in the treatment of ED after RP. Traditional treatment methods include the use of autologous nerve transplantation, such as sural nerve transplantation, which although effective, requires a second surgery and sacrifices healthy nerve tissue, bringing certain risks of complications (138). In recent years, researchers have explored the use of decellularized nerve scaffolds as an alternative, which removes the cellular components of the donor nerve, leaving only the extracellular matrix, thereby reducing immune rejection reactions (139). Although animal experiments have shown that decellularized nerve scaffolds can effectively promote nerve regeneration and restore EF, comparable to autologous nerve grafting, there is currently a lack of large-scale clinical trial data in humans to confirm the efficacy and safety of decellularized nerve scaffolds (140). Nerve transplantation also involves high surgical complexity and the need for a second surgery. Despite these challenges, nerve transplantation still points to a new direction for the treatment of ED, potentially reducing the burden on patients and improving therapeutic outcomes.

Stem cell and platelet-rich plasma (PRP) therapy

Undifferentiated or partially differentiated stem cells can self-renew and differentiate into other types of cells. Albersen et al. conducted an experiment where adipose tissue-derived stem cells (ADSCs) were injected into the corpora cavernosa of rats that had experienced cavernous nerve injury (CNI). The findings indicated several positive outcomes in the ADSC-injected group: an enhanced presence of nNOS in the dorsal penile nerves, a higher density of smooth muscle cells within the cavernous tissue, reduced apoptosis, diminished fibrosis, increased intracavernous pressure, and overall improved EF (141). Meanwhile, Sun et al. injected bone marrow mesenchymal stem cells (BM-MSCs) into the corpora cavernosa of the rats penis. The outcomes of the experiment demonstrated that BM-MSCs could upregulate the production of VEGF, nerve growth factor, and brain-derived neurotrophic factor (BDNF); protect nerve growth factor-positive nerve fibers; and raise the level of nNOS (142). Clinical trials also support the improvement of ED by stem cell therapy. Using various concentrations of BM-MNCs, Yiou et al. conducted a phase I–II clinical trial on 12 patients with ED after RP who were not responding to PDE-5i treatment. Evaluation of the results showed that patients in the treatment group had significantly improved sexual satisfaction and EF (143). Moreover, Haahr et al. reported that 8 of 17 patients who had undergone RP and were unresponsive to conventional therapy exhibited improvement in their EF after receiving an injection of ADSCs (144). Studies have shown that stem cell therapy for ED has almost no side effects, with only two clinical trials reporting minor effects at the injection site (transient redness, scrotal and penile hematoma), all of which resolved spontaneously (82,144,145). PRP is a plasma product extracted from autologous blood, rich in high concentrations of platelets and containing various cytokines, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF). Clinical studies have shown that the level of PDGF in the serum of patients with ED is significantly elevated, while the levels of VEGF and TGF-β are approximately 1.5 times lower than in the normal population (146,147). Current literature supports that PRP treatment for ED is safe (148,149), and numerous preclinical (150) and clinical studies (151,152) have demonstrated the positive effects of PRP on EF. However, in a study by Masterson et al., after injecting PRP into the corpora cavernosa of ED patients, it was found that one month later, the average IIEF-5 score for those treated with PRP increased from 17.4 (95% confidence interval: 15.8–19.0) to 21 (17.9–24.0), while the placebo group’s scores increased from 18.6 (17.3–19.8) to 21.6 (19.1–24.1), with no significant difference observed between the two groups (153). This outcome may be related to individual differences in the severity of ED among patients, suggesting that different concentrations of PRP may be required for treatment. In the context of ED following PCa surgery, stem cell and PRP therapies still require in-depth research to determine the optimal preparation methods, dosage, and routes of administration. Furthermore, these treatment methods necessitate specific technical and equipment support, which to some extent limits their application in large-scale clinical trials.

Gene and targeted therapy

Gene therapy is a promising tool for the precision diagnosis and treatment for ED in the future. A study has shown that the injection of BDNF or VEGF can significantly restore the nNOS-positive nerve fibers in rats (154). BDNF not only promotes the formation of Schwann cell myelin sheaths but also repairs the cavernous nerves through the AKT/STAT pathway (155). Yin et al. used Ninj1 antibody (Ninj1-Ab) to treat rats with bilateral CNI. The results showed that Ninj1-Ab significantly increased the content of NOS and neurofilament in penile neurons by upregulating angiogenin-1 and downregulating angiogenin-2, inducing the proliferation of cavernous endothelial cells and the phosphorylation of Akt and endothelial NOS and reducing the apoptosis of endothelial cells. A dose of 2.5 µg/20 µL of Ninj1-Ab restored EF in 91% of rats with CNI-induced ED (CNIED) (156). RhoA signal transduction regulates smooth muscle contraction by activating Rho-associated protein kinase (ROCK), promoting the inactivation of myosin light chain phosphatase (MLCP) and inhibiting the sensitivity of smooth muscle cells to Ca²⁺ (157). Currently, there is controversy concerning the expression levels of ROCK1 and ROCK2 in CNIED (158,159). Sauzeau and Sopko’s respective studies indicated that Y-27632 (ROCK-1 inhibitor) can upregulate the expression of nNOS and endothelial NOS in the penis of CNIED rats, inhibit the apoptosis of nNOS-positive axons, and help protect the EF of rats (160,161). Gene therapy can precisely regulate the expression of key genes and has shown great potential in the field of ED treatment. However, its high cost and the need for personalized customization have limited the widespread adoption of gene therapy at this stage.

TCM and Chinese herbal extracts

In 1998, the TCM formula, BetterMAN, debuted in the American market, igniting a surge of interest in the use of TCM for the treatment of ED. Post-prostatectomy ED encompasses a variety of pathological pathways (162). While modern Western medications tend to focus on single-target therapies, TCM, with its multitargeted interventional approach, can more effectively address the complex etiologies of ED following PCa treatment. A substantial body of animal and clinical experiments has indicated that TCM and its extracts can treat ED (Table 2). Unfortunately, no multicenter RCTs have examined the use of TCM for ED in patients with PCa, and future large-scale, double-blinded, RCTs are necessary for validation in this context. TCM holds immense potential in the treatment of ED, and further exploration of ED treatment with TCM integrated with modern technological advancements may provide considerable benefit to patients.

Conclusions

With the development of medical technology, the treatment of PCa is gradually moving toward more precise and personalized plans for reducing the impact on patients’ EF. The popularization of PSA screening has improved the early diagnosis rate of PCa, making AS the preferred option for low-risk patients, as it significantly reduces the incidence of ED compared to active treatment. The optimization of equipment and technology for RT and cryotherapy, the improvement of surgical techniques, and the continuous evolution of intraoperative nerve monitoring technology have also mitigated the adverse effects on EF. Immunotherapy and chemotherapy may elevate the risk of ED, but determining their exact impact still requires additional clinical investigation. ADT therapy appears to invariably lead to ED, and further exploration of novel treatment plans is needed.

With the continuous advancement of biomedical technology, emerging treatment strategies have great potential. Physical energy therapy, such as LI-ESWT and PEMST, represent a new direction in the noninvasive treatment of ED, as it can promote angiogenesis and reduce inflammatory responses. Tissue engineering technology, especially that related to artificial penile scaffolds, is a source of optimism in the future treatment of ED. Nerve transplantation technology, through the application of autologous nerves or decellularized nerve scaffolds, has shown noteworthy potential in restoring EF after PCa surgery. Gene therapy, by precisely regulating molecular signaling pathways, may provide new targets and methods for the treatment of ED. Stem cell therapy, with its strong regenerative ability, is expected to significantly improve the nerve and tissue damage caused by surgery or other treatment methods, thereby restoring EF. PRP therapy aids in the functional recovery of patients with ED. In addition, the application of TCM in the treatment of ED has gradually received increased attention, and its unique advantage of multitargeted intervention may supplement Western therapy for patients with PCa. All emerging treatment modalities have their particular limitations, such as the need for personalized customization, high cost, and complex operation.

While this narrative review provides an in-depth analysis of the relationship between PCa treatment and ED, it acknowledges certain limitations. Specifically, our literature search may not have comprehensively covered all relevant studies, risking the omission of key literature. Furthermore, the subjectivity inherent in the review process may have influenced the selection and interpretation of the literature. Despite these limitations, we recognize the complex relationship between PCa treatment and ED, as well as the efficacy of emerging treatment methods on ED and the barriers to their large-scale clinical application. Therefore, we emphasize the development of more effective and comprehensive ED treatment plans for PCa patients through multidisciplinary collaboration and innovation, aiming to enhance their quality of life and improve their psychological well-being and intimate relationships.

Acknowledgments

Funding: This study was funded by the Zhejiang Province Traditional Chinese Medicine Prevention and Control Major Disease Research Plan (No. 2018ZY007), the National Natural Science Foundation of China (Nos. 82174376 and 82074433), and the Natural Science Foundation of Zhejiang Province (No. LGF20H270002).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-514/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-514/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-514/coif). All authors report that this study was funded by the Zhejiang Province Traditional Chinese Medicine Prevention and Control Major Disease Research Plan (No. 2018ZY007), the National Natural Science Foundation of China (Nos. 82174376 and 82074433), and the Natural Science Foundation of Zhejiang Province (No. LGF20H270002). B.L. reports that he serves as the next chairman of the Urology Branch of the Chinese Association of Integrated Traditional Chinese and Western Medicine without compensation. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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