Clinical outcomes of holmium laser enucleation of the prostate: A large prospective registry-based patient cohort study under regular follow-up protocol.

PURPOSE: To evaluate the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) in a large prospective cohort of patients with benign prostatic hyperplasia (BPH) through systematic follow-up at a single institution. MATERIALS AND METHODS: Clinical outcomes were analyzed between August 2008 and June 2022. Patients were followed-up at 2 weeks, 3 months and 6 months postoperatively. RESULTS: A total of 3,000 patients (mean age, 69.6±7.7 years) underwent HoLEP. Baseline total International Prostate Symptom Score (IPSS) was 19.3±7.7 and maximum flow rate (Qmax) was 9.4±4.8 mL/s. Mean total prostate volume was 67.7±3.4 mL. Total operation time was 60.7±31.5 minutes, and catheterization time was 1.0 days (range, 1.0-1.0 days). At 6 months postoperatively, the total IPSS decreased to 6.6±5.8 and Qmax increased to 22.2±11.3 mL/s. Complications at 6 months postoperatively included stress urinary incontinence (SUI) in 36 patients (1.9%), urgency urinary incontinence (UUI) in 25 (1.3%), bladder neck contracture (BNC) requiring transurethral incision (TUI) in 16 (0.5%), and urethral stricture in 29 (1.0%). Eleven patients (0.4%) with prostatic fossa stones required stone removal. Sixty-one patients (2.0%) required secondary surgery (transurethral coagulation, 16 [0.5%]; TUI for BNC, 16 [0.5%]; stone removal for prostatic fossa stones, 11 [0.4%]; and endoscopic internal urethrotomy for urethral stricture, 18 [0.6%]). CONCLUSIONS: Mid-term follow-up results after HoLEP in BPH patients showed excellent efficacy and low complication rates. Unlike previous reports, the incidence of SUI and UUI after HoLEP was low, but the occurrence of de novo stone formation in prostatic fossa was notable.

Risk Factors of Salvage Procedure for Refractory Morcellation During Holmium Laser Enucleation of the Prostate.

PURPOSE: We aimed to identify the risk factors for salvage procedure (SP) required for refractory adenomatous tissue resistant to morcellation during holmium laser enucleation of the prostate (HoLEP). METHODS: Patients who underwent HoLEP between January 2010 and April 2020 at Seoul National University Hospital were analyzed. SPs were defined as cases of conversion to resection of the prostatic tissue using an electrosurgical loop after morcellation or secondary morcellation a few days after surgery or conversion to open cystotomy. RESULTS: Among a total of 2,427 patients, 260 were identified as having SP (SP group) (transurethral resection-nodule [n = 250, 96.1%], secondary morcellation a few days after surgery [n = 9, 3.5%], and conversion to open cystotomy [n = 1, 0.4%]). Patients in the SP group were older and had higher 5-α reductase inhibitors use, higher prostate-specific antigen, larger total prostate volume, and larger transition zone volume (TZV) than those in the non-SP group. In the multivariable logistic regression analysis, only age and TZV were associated with SP. Compared to 40s and 50s, the odds ratios (ORs) were 3.84 in 60s (95% confidence interval [CI] 1.37-10.78, P = 0.011), 4.53 in 70s (95% CI, 1.62-12.62, P = 0.004), and 6.59 in 80s or older (95% CI, 2.23-19.46, P = 0.001). The ORs of the SP were analyzed per TZV quartile. Compared to TZV ≤ 20.3 mL, the OR was 3.75 in 32.0 mL < TZV ≤ 50.4 mL (95% CI, 2.00-7.04, P < 0.001) and 8.25 in 50.4 mL < TZV (95% CI, 4.06-16.77, P < 0.001). CONCLUSION: The risk of refractory morcellation increased in patients aged > 60 years or those with TZV > 32 mL. In order to more efficiently remove these resistant adenomas, it is necessary to develop more efficient morcellators in the future.

Does Preoperative Bladder Compliance Affect Long-Term Functional Outcomes after Laser Prostatectomy?

PURPOSE: We assessed the effects of preoperative bladder compliance on the long-term functional outcomes, especially focused on postoperative storage symptom changes, after laser prostatectomy. MATERIALS AND METHODS: From January 2008 to March 2014, 1,608 men who underwent laser prostatectomy, including holmium laser enucleation or photo-vaporization of the prostate, were included in the analysis. We divided patients into 3 groups according to bladder compliance on a baseline urodynamic study: <12.5, 12.5-25, ≥25 mL/cmH2O. A multivariable analysis was performed to determine the impact of bladder compliance on changes in long-term functional outcomes after laser prostatectomy. RESULTS: Bladder compliance was less than 12.5 mL/cmH2O in 50 (3.1%), 12.5-25 mL/cmH2O in 232 (14.4%) patients. As bladder compliance decreased, the baseline International Prostate Symptom (IPSS) total score and storage sub-score were increased; the voiding sub-score remain unchanged. At postoperative 12 and 36 months, absolute improvements in the IPSS total score and storage sub-score were higher in <12.5 mL/cmH2O group compared to other groups, although those were equivalent at postoperative 1 months. On the multivariable analysis, decreased bladder compliance <12.5 mL/cmH2O was significantly associated with superior improvement in storage sub-score at postoperative 36 months, although it was not associated with voiding sub-score. CONCLUSIONS: In patients with preoperative bladder compliance <12.5 mL/cmH2O, storage symptoms could be further improved at 36 months after laser prostatectomy compared to others. Thus, laser prostatectomy could be a considerable treatment option for patients with severely decreased bladder compliance.

Natural history of incidentally diagnosed prostate cancer after holmium laser enucleation of the prostate.

OBJECTIVES: There is no consensus on the management plan for incidental prostate cancer (IPCa) after holmium laser enucleation of the prostate (HoLEP). This study aims to investigate the natural course of this disease and suggest appropriate treatment in real clinical practice. METHODS: The medical records of a prospective cohort of patients with LUTS/BPH who underwent HoLEP between July 2008 and December 2020 at Seoul National University Hospital were retrospectively reviewed. Patients who underwent HoLEP for palliative purpose of prostate cancer control were excluded. The natural history of IPCa was assessed by the clinician in a descriptive manner for each treatment option. RESULTS: Among 2630 patients, 141 (5.4%) were diagnosed with IPCa after HoLEP. Pathologic T stage and magnetic resonance imaging results were highly associated with the physician's primary treatment decision-making for IPCa. Active surveillance (AS) was performed in 80% of patients, of whom 90% underwent follow-up without intervention, while the remaining 10% underwent deferred active treatment with a median follow-up of 46.3 months due to International Society of Urological Pathology grade group upgrading or increasing core involvement percentage. Meanwhile, 20% of patients underwent immediate active treatment. With a median follow-up period of 88.3 months after treatment, only one of 25 patients had biochemical recurrence. CONCLUSIONS: The incidence of IPCa after HoLEP was 5.4%, and among these, approximately 20% proceeded with immediate definitive therapy and an additional 6% ultimately received definitive therapy within a median of 4 years of AS but showed excellent oncological outcomes.

Publisher Correction: Quality of life after photo-selective vaporization and holmium-laser enucleation of the prostate: 5-year outcomes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Quality of life after photo-selective vaporization and holmium-laser enucleation of the prostate: 5-year outcomes.

This study was aimed to compare serial long-term postoperative changes in quality-of-life (QoL) between photoselective-vaporization (PVP) using 120W-High-Performance-System and holmium-laser-enucleation (HoLEP) in benign-prostatic-hyperplasia (BPH) patients and to identify factors influencing the QoL improvement at the short-term, mid-term and long-term follow-up visits after surgery. We analyzed 1,193 patients with a baseline QoL-index ≥2 who underwent PVP (n = 439) or HoLEP (n = 754). Surgical outcomes were serially compared between the two groups at up to 60-months using the International-Prostatic-Symptom-Score (I-PSS), uroflowmetry, and serum PSA. We used logistic regression analysis to identify predictors of QoL improvement (a reduction in the QoL-index ≥50% compared with baseline) at the short-term (12-months), mid-term (36-months), and long term (60-months) follow-up after surgery. In both groups, the QoL-index was decreased throughout the entire follow-up period compared with that at baseline. There were no significant differences in postoperative changes from the baseline QoL-index between the two groups during the 48-month follow-up, except at 60-months. The degree of improvement in QoL at 60-months after HoLEP was greater than that after PVP. A lower baseline storage-symptom-subscore and a higher bladder-outlet-obstruction-index (BOOI) were independent factors influencing QoL improvement at the short-term. No independent factor influences QoL improvement at the mid- or long-term.

Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury.

OBJECTIVE: To determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. METHODS: Sixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. RESULTS: The CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. CONCLUSION: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction.

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg-1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg-1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg-1 LIMK2i and 20.0 mg kg-1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

Chronic administration of LIMK2 inhibitors alleviates cavernosal veno-occlusive dysfunction through suppression of cavernosal fibrosis in a rat model of erectile dysfunction after cavernosal nerve injury.

We evaluated whether chronic administration of LIMK2-inhibitors could improve erectile function by alleviating CVOD through suppressing cavernosal fibrosis in a rat model of cavernosal nerve crush-injury (CNCI). Forty-two 12-week-old rats were equally categorized into the three groups: sham-surgery (S), CNCI (I), and CNCI treated with LIMK2-inhibitors (L). The L-group was treated with daily intraperitoneal injection of LIMK2-inhibitors (10.0 mg/kg) for 30-days after surgery. Erectile function was assessed using dynamic-infusion-cavernosometry (DIC). Penile tissue was processed for Masson's-trichrome staining, Western-blotting, and double immunofluorescence. The I-group showed significantly higher maintenance and drop rates as well as lower papaverine response, compared to the S-group. Chronic inhibition of LIMK2 in the L-group significantly improved the DIC parameters compared to those in the I-group, although the parameters were not completely restored to normal control values. Also, the I-group showed a reduced smooth muscle (SM)-to-collagen ratio, decreased immunohistochemical staining for α-SM-actin, increased number of fibroblasts positive for phosphorylated Cofilin, increased LIMK2/Cofilin phosphorylation and increased protein expression of Collagen-1 or Fibronectin, compared to the S-group. The L-group showed significant improvements in SM/collagen ratio and the deposition of Collagen-1 or Fibronectin compared to the I-group, although not completely normalized. According to the densitometry and confocal microscopy results, the L-group showed restoration of LIMK2/Cofilin phosphorylation and amount of fibroblasts positive for phosphorylated Cofilin to the normal control value. In conclusion, chronic inhibition of LIMK2 can improve CVOD and ED by alleviating cavernosal fibrosis via normalizing the LIMK2/Cofilin pathway.

Comparison of Improving Effects for Diabetic Erectile Dysfunction according to the Anti-Glycemic Agents: Phlorizin and Insulin.

PURPOSE: To compare the improving effects of diabetic erectile dysfunction with two anti-glycemic agents; phlorizin and insulin. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were divided into four groups (n=15 in each group): normal control (C), untreated diabetic rats (D), and diabetic rats treated by phlorizin (P) or insulin (I). Ten weeks after the diabetic induction using an injection of streptozotocin (55 mg/kg), four weeks of diabetic control was conducted. Erectile response, Western blot, and immunohistochemistry were assessed. RESULTS: During the experiment, the C-group showed continuous weight gain, while the other groups suffered from weight loss. After start of diabetic control, the body weight of I-group was increased; whereas, there was no meaningful change in the P-group. Meanwhile, comparable blood glucose levels were achieved in the P- and I-groups. The erectile response was markedly decreased in the D-group, whereas the P- and I-groups were similar as good as the C-group. In addition, D-group showed the significant decrease in the cavernosal smooth muscle content and increased apoptosis. Platelet endothelial cell adhesion molecule-1 protein expression, phosphorylation of endothelial nitric oxide synthase and myosin phosphatase target subunit 1 were significantly distorted in the D-group, while the P- and I-groups were comparable with the C-group. CONCLUSIONS: Phlorizin treatment resulted in the improvement of erectile function as same as insulin despite the lack of anabolic weight gains. These results suggest that control of blood glucose level rather than a type of anti-glycemic agents is more important for the prevention and treatment of diabetic erectile dysfunction.

Effect of preoperative detrusor underactivity on long-term surgical outcomes of photovaporization and holmium laser enucleation in men with benign prostatic hyperplasia: a lesson from 5-year serial follow-up data.

OBJECTIVES: To investigate the impact of preoperative detrusor underactivity (DU) on serial treatment outcomes over the course of 5 years after photovaporization (PV) or holmium laser enucleation (HoLEP) in patients with benign prostatic hyperplasia (BPH), to compare its impact after PV vs HoLEP, and to identify predictors of long-term lower urinary tract symptoms (LUTS) improvement. MATERIALS AND METHODS: This study involved 245 patients with BPH who had complete 5-year follow-up data (PV using 120W-HPS, n = 143, HoLEP, n = 102), grouped as follows: PV-HPS-DU(+), n = 114; PV-HPS-DU(-), n = 29; HoLEP-DU(+), n = 56; and HoLEP-DU(-), n = 46. Bladder contractility index (BCI) < 100 was regarded as DU. Serial treatment outcomes for the International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry and serum PSA level at 6 months, and at 1, 2, 3, 4 and 5 years after surgery, were compared among the groups. LUTS improvement was defined as a reduction in total IPSS of ≥50% relative to baseline. RESULTS: Improvement in total IPSS, quality of life (QoL) index and post-void residual urine volume (PVR) in the PV-HPS-DU(+) and PV-HPS-DU(-) groups were maintained up to 5 years after PV, except for maximum urinary flow rate (Qmax ) and bladder voiding efficiency. In the HoLEP-DU(+) and HoLEP-DU(-) groups, improvements in all outcome variables were maintained up to 5 years after HoLEP. Deteriorations in subtotal voiding symptom score, total IPSS and Qmax with time during the long-term period after surgery were more pronounced in the PV-HPS-DU(+) and HoLEP-DU(+) groups than in the PV-HPS-DU(-) and HoLEP-DU(-) groups. Reductions in subtotal voiding symptom score, total IPSS, QoL index, and serum PSA were greater in the HoLEP-DU(+) group than in the PV-HPS-DU(+) group throughout follow-up. The type of surgery (HoLEP vs PV) and higher baseline BCI were independent predictors of LUTS improvement at 5 years after surgery. CONCLUSION: Generally, improvement of micturition symptoms, QoL and PVR in patients with DU appears to be maintained up to 5 years after PV or HoLEP. Deterioration of voiding symptoms and urinary flow rate at long-term follow-up visits after PV or HoLEP was more pronounced in patients with LUTS/BPH with DU than in those without DU. Patients with BPH with DU may benefit from more complete removal of prostatic adenoma by HoLEP and greater baseline bladder contractility in terms of micturition symptoms and QoL.

Effects of combined growth hormone and testosterone treatments in a rat model of micropenis.

Although it is well known that penile growth is dependent on androgens, few clinical studies have reported successful treatment of micropenis with testosterone, likely due to concerns regarding the efficacy and safety of prolonged testosterone use. Thus, we assessed the synergenic effects of growth hormone (GH) treatments with and without testosterone on phallic growth in a rat model of micropenis. Fifty Sprague-Dawley rats were assigned to control (C), microphallus (MP), testosterone (T), GH (G) and GH plus testosterone (GT) treatment groups, and microphallus was induced by secondary hypogonadism. Pre-pubertal treatments with testosterone, GH or the combination were initiated from 7 days after birth and were maintained until 12 weeks of age. To assess the efficacy of treatments, phallic dimensions were determined and histological markers of cavernosal integrity were evaluated. Skeletal and gonadal safety profiles of the treatments were then assessed according to right tibial lengths and testicular weights, respectively. No monotreatments normalised penile dimensions, whereas combination treatments led to complete restoration. The combination treatment also prevented decreases in histological indicators of cavernosal integrity, including smooth muscle actin and collagen III expression levels and fat globule accumulation and sinusoidal density. These synergenic effects of GH treatments on penile growth may follow changes in androgen receptor expression levels and were accompanied by decreased testicular volume losses. Although the physiological conditions of phallic growth differ between humans and rats, this proof-of-concept study provides a strategy for circumventing the problems of testosterone monotherapy for human micropenis.

Self-assessed goal achievement (SAGA) after Holmium laser enucleation of the prostate (HoLEP): Association with patients' postoperative satisfaction.

This study aimed to determine serial changes in self-assessed goal achievement (SAGA) and treatment satisfaction after HoLEP, to identify correlations between the two, and to compare them with results assessed by traditional outcome measures. For a total of 170 patients, outcomes were evaluated serially at postoperative 1-, 3-, 6-, and 12-months using IPSS, OABSS, SAGA questionnaires and uroflowmetry. The SAGA questionnaire consisted of five questions including one open-ended question (self-assessed goals and degree of SAGA) and another question regarding treatment satisfaction. The number of self-assessed treatment goals was two or more in 74.1% of the patients. Most common treatment goal was relief from straining/hesitancy, followed by increased daytime frequency, nocturia and feeling of incomplete emptying. Degree of achievement for the first or second goal and treatment satisfaction tended to increase with time throughout the follow-up period. Patients with the greatest treatment satisfaction scores showed greater improvement by traditional outcome parameters including quality of life (QOL) index, total OABSS, maximum flow rate (Qmax), post-void residual urine volume (PVR) and bladder voiding efficiency (BVE) compared to those without treatment satisfaction. After adjusting for other influential variables, the improvements in subjective outcome parameters including total IPSS, QOL index and total OABSS were significantly associated with treatment satisfaction, but improvements in objective outcome parameters including Qmax, PVR and BVE were not. In addition, the degree of SAGA for the first goal or second goal was more predictive in determining treatment satisfaction than the traditional outcome measures. In conclusion, treatment goals of patients with lower urinary tract symptoms (LUTS)/BPH vary from individual to individual. The degree of SAGA and treatment satisfaction for HoLEP tends to increase with time throughout the follow-up period. Compared to the traditional outcome measures, the degree of goal achievement can be more predictive when assessing patient-centered outcomes such as treatment satisfaction.

Suppression of Cavernosal Fibrosis in a Rat Model.

INTRODUCTION: Cavernosal fibrosis is an important pathologic condition leading to erectile dysfunction (ED). The etiologies of cavernosal fibrosis include aging, diabetes mellitus, castration, cavernosal nerve injury during radical prostatectomy, hypertension, and Peyronie disease. AIMS: To summarize published studies investigating suppression of cavernosal fibrosis in rat models of ED of various etiologies. METHODS: A literature search was conducted using PubMed. Relevant studies were identified using search terms such as erectile dysfunction, penis, fibrosis, and rat models. MAIN OUTCOME MEASURES: We reviewed representative literature studies on the mechanisms and suppression of cavernosal fibrosis in rat models of ED. RESULTS: The underlying mechanisms and potential therapeutic strategies suggested thus far for cavernosal fibrosis in rat models of ED were as follows. For age-related ED involving oxidative stress and tumor growth factor-ß1 (TGF-ß1)-driven pathways such as RhoA-ROCK1-LIMK2-cofilin or p42-44 and mitogen-activated protein kinase, proposed therapeutic strategies included phosphodiesterase type 5 inhibitors (PDE5Is), kallikrein-kinin system stimulators, and calorie restriction. For diabetes-related ED involving angiotensin-II- and TGF-ß1-driven Smad and non-Smad pathways, TGF-ß1-Wnt10b, and histone deacetylase (HDAC)-TGF-ß1 pathways, positive therapeutic results were obtained with PDE5Is, TGF-ß1 antagonists, HDAC inhibitors, antioxidants, sphingosine-1-phosphate receptor modulators (fingolimod), angiotensin-II antagonists, stem cell therapy, and antidiabetic drugs. For cavernosal nerve injury-associated ED involving TGF-ß1-driven pathways (Smad or RhoA-ROCK1-LIMK2-cofilin), Sonic hedgehog signaling, angiotensin-II-Smad, and HDAC4-TGF-ß1-Smad signaling triggered by cavernosal hypoxia, PDE5Is, angiotensin-II antagonists, stem cell therapy, HDAC inhibitors, Sonic hedgehog administration, ROCK inhibitors, and LIMK2 inhibitors have shown positive results. For testosterone deficiency-associated ED, TGF-ß1-driven pathways were found to be responsive to testosterone supplementation. For hypertensive ED, positive therapeutic results were obtained with angiotensin-II antagonists. For Peyronie disease involving TGF-ß1 or myostatin signaling, proposed therapeutic strategies included intra-tunical injection of TGF-ß receptor inhibitors or adipose tissue-derived stem cells and HDAC2 small hairpin RNA. CONCLUSION: Several signaling pathways appear to be responsible for the development of cavernosal fibrosis related to ED of various etiologies. Some therapeutic success has been achieved in animal models, but further research focusing on mechanism-specific targeted therapies is needed. Cho MC, Song WH, Paick J-S. Suppression of Cavernosal Fibrosis in a Rat Model. Sex Med Rev 2018;6:572-582.

Role of inhibiting LIM-kinase2 in improving erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury.

We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho-associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2.5, 5.0, and 10.0 mg kg-1 body weight, respectively) for 1 week after surgery. The erectile response was assessed using electrostimulation at 1 week, postoperatively. Penile tissues were processed for Masson's trichrome staining, double immunofluorescence, and Western blot assay. Erectile responses in the H group improved compared with the I group, while the M group showed only partial improvement. A significantly decreased smooth muscle/collagen ratio and an increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The M and H groups revealed significant improvements in histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The inhibition of LIMK2 did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, whereas it did not in the M group. However, the L group did not exhibit such improvements. Our data suggest that the inhibition of LIMK2, particularly with administration of 10.0 mg kg-1 body weight LIMK2i, can improve corporal fibrosis and erectile function by normalizing the LIMK2/Cofilin pathway.

Long-Term Outcomes of Laser Prostatectomy for Storage Symptoms: Comparison of Serial 5-Year Followup Data between High Performance System Photoselective Vaporization and Holmium Laser Enucleation of the Prostate.

PURPOSE: We compared long-term storage symptom outcomes between photoselective laser vaporization of the prostate with a 120 W high performance system and holmium laser enucleation of the prostate. We also determined factors influencing postoperative improvement of storage symptoms in the long term. MATERIALS AND METHODS: Included in our study were 266 men, including 165 treated with prostate photoselective laser vaporization using a 120 W high performance system and 101 treated with holmium laser enucleation of the prostate, on whom 60-month followup data were available. Outcomes were assessed serially 6, 12, 24, 36, 48 and 60 months postoperatively using the International Prostate Symptom Score, uroflowmetry and the serum prostate specific antigen level. Postoperative improvement in storage symptoms was defined as a 50% or greater reduction in the subtotal storage symptom score at each followup visit after surgery compared to baseline. RESULTS: Improvements in frequency, urgency, nocturia, subtotal storage symptom scores and the quality of life index were maintained up to 60 months after photoselective laser vaporization or holmium laser enucleation of the prostate. There was no difference in the degree of improvement in storage symptoms or the percent of patients with postoperative improvement in storage symptoms between the 2 groups throughout the long-term followup. However, the holmium laser group showed greater improvement in voiding symptoms and quality of life than the laser vaporization group. On logistic regression analysis a higher baseline subtotal storage symptom score and a higher BOOI (Bladder Outlet Obstruction Index) were the factors influencing the improvement in storage symptoms 5 years after prostate photoselective laser vaporization or holmium laser enucleation. CONCLUSIONS: Our serial followup data suggest that storage symptom improvement was maintained throughout the long-term postoperative period for prostate photoselective laser vaporization with a 120 W high performance system and holmium laser enucleation without any difference between the 2 surgeries. Also, more severe storage symptoms at baseline and a more severe BOOI predicted improved storage symptoms in the long term after each surgery.

Inhibition of Jun N-terminal Kinase Improves Erectile Function by Alleviation of Cavernosal Apoptosis in a Rat Model of Cavernous Nerve Injury.

OBJECTIVE: To determine whether Jun N-terminal kinase (JNK) inhibition could alleviate erectile dysfunction (ED) through suppressing cavernosal apoptosis in a rat model of carvernosal nerve crush injury (CNCI), thereby providing potential therapeutic strategy for alleviating postradical prostatectomy ED. MATERIALS AND METHODS: Fifty-six 11-week-old male Sprague-Dawley rats were categorized equally into the following 4 groups: (1) sham surgery (S), (2) CNCI (I), (3) CNCI treated with low-dose JNK inhibitor (L), and (4) CNCI treated with high-dose JNK inhibitor (H). The L and H groups received daily intraperitoneal injection of JNK inhibitors (1.0 mg/kg for the L group and 10.0 mg/kg for the H group) for 2 weeks starting from the following day after surgery. Erectile response, Western blot, and immunohistochemistry were assessed. RESULTS: At 2 weeks after surgery, intracavernous pressure-mean arterial pressure and area under the curve-mean arterial pressure in group I were significantly decreased compared with those in group S. Erectile responses in group H were significantly improved compared with those in group I. Group I showed decreased smooth muscle (SM) content, increased apoptosis, increased apoptotic or SM cells positive for phosphorylated c-Jun, increased c-Jun phosphorylation, and decreased Bcl2-to-Bax ratio compared with group S. Group H showed significant improvements in histologic alterations and dysregulation of the JNK-driven pathway. CONCLUSION: Our data suggest that JNK inhibition can improve erectile function by alleviating cavernosal apoptosis through restoring the JNK-related pathway toward normal. Thus, an early therapeutic strategy targeting the JNK pathway might be able to alleviate cavernosal SM apoptosis and postradical prostatectomy ED caused by cavernous nerve injury.

Role of Jun amino-terminal kinase (JNK) in apoptosis of cavernosal tissue during acute phase after cavernosal nerve injury.

The present study aimed to identify which mitogen-activated protein kinase (p38 or Jun amino-terminal kinase [JNK]) was involved in cavernosal apoptosis during the acute phase after cavernosal nerve crush injury (CNCI) in rats to ameliorate apoptosis of cavernosal tissue, such as smooth muscle (SM). A total of twenty 10-week-old male Sprague-Dawley rats were divided equally into two groups: sham surgery (S) and CNCI (I). The I group approximated the clinical situation of men undergoing radical prostatectomy using two 60-second compressions of both CNs with a microsurgical vascular clamp. At 2-week postinjury, erectile response was assessed using electrostimulation. Penile tissues were harvested for immunohistochemistry analysis of alpha-SM actin (α-SMA), western blot analysis, and double immunofluorescence analysis of α-SMA and phosphorylated p38 or JNK, as well as double immunofluorescent of TUNEL and phosphorylated p38 or JNK. At 2-week postinjury, the I group had a significantly lower intracavernous pressure (ICP)/mean arterial pressure (MAP) and a lower area under the curve (AUC)/MAP than the S group. The I group also exhibited decreased immunohistochemical staining of α-SMA, an increase in the number of SM cells positive for phosphorylated JNK, an increased number of apoptotic cells positive for phosphorylated JNK, and increased JNK phosphorylation compared with the S group. However, there was no significant difference in p38 phosphorylation expression or the number of SM cells positive for phosphorylated p38 between the two groups. In conclusion, our data suggest that JNK, not p38, is involved in cavernosal apoptosis during the acute phase after partial CN damage.

Patient-reported ejaculatory function and satisfaction in men with lower urinary tract symptoms/benign prostatic hyperplasia.

This study aimed to investigate perceived ejaculatory function/satisfaction before treatment for lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) and to identify associations between specific categories of ejaculatory dysfunctions (EjDs) and LUTS. A total of 1574 treatment-naïve men with LUTS/BPH were included in this study. All patients underwent routine evaluation for LUTS/BPH including the International Index of Erectile Function and a 5-item questionnaire developed to assess ejaculatory volume/force/pain/satisfaction/latency time. Patients who had sexual intercourse over the past 4 weeks were classified as sexually active group. A total of 783 patients were categorized as sexually active group. Decreased ejaculatory volume and force were reported by 53.4% and 55.7% of 783 sexually active men, respectively. There was a strong correlation between ejaculatory volume and force. Ejaculatory pain/discomfort, premature ejaculation (PE), and delayed ejaculation (DE) were reported in 41.0%, 16.3%, and 41.4% of the patients, respectively. Over 40.0% of men without decreased ejaculation volume/force were satisfied with ejaculatory function, whereas approximately 6.0% of men with decreased volume/force were satisfied with ejaculatory function. About 30.0% of men with decreased volume/force had orgasmic dysfunction, while approximately 10.0% of men without decreased volume/force did. Decreased ejaculatory volume or force was associated with LUTS severity after adjusting for other influential factors including testosterone level, erectile function, and prostate size on ultrasonography, but PE or DE or ejaculatory pain/discomfort was not. In conclusion, a considerable portion of men with LUTS/BPH appear to have a variety of EjDs. Ejaculatory volume/force and satisfaction/orgasm do not always appear to be concordant. Ejaculatory volume or force is independently associated with LUTS severity, whereas PE or DE or ejaculatory pain/discomfort is not.

Can preoperative detrusor underactivity influence surgical outcomes of 120 W HPS vaporization of the prostate (PVP) or holmium laser enucleation of the prostate (HoLEP)? A serial 3-year follow-up study.

AIMS: To determine the influence of preoperative detrusor underactivity (DU) on serial long-term outcomes of HPS/PVP or HoLEP for LUTS/BPH, and to compare the influence between the two surgeries. METHODS: A total of 382 men, who underwent 120W-HPS/PVP or HoLEP for LUTS/BPH and for whom 36-month follow-up data were available, were classified into four groups: HPS with DU (n = 145), HPS without DU (n = 44), HoLEP with DU (n = 105), and HoLEP without DU (n = 88). DU was defined as bladder contractility index of <100. Surgical outcomes were assessed at postoperative 6, 12, 24, and 36 months using IPSS, uroflowmetry, and serum PSA. RESULTS: All four groups maintained improvements in voiding symptom score (VSS), storage symptom score, total-IPSS, QOL index, maximum flow rate (Qmax), post-void residual urine volume (PVR), and bladder voiding efficiency (BVE) compared with baseline up to 3 years postoperatively. There were no significant differences in improvements of postoperative IPSS parameters including QOL index between men with and without DU throughout the follow-up period after HPS or HoLEP. In men with DU, there were no significant differences in improvements of postoperative QOL index, Qmax, PVR, or BVE between HPS and HoLEP groups throughout the follow-up period, except for VSS and total IPSS. Serum PSA reductions after HoLEP were greater than after PVP. CONCLUSIONS: Improvements in LUTS, Qmax, and BVE can maintain up to 3 years after HPS or HoLEP for LUTS/BPH, irrespective of the presence or absence of preoperative DU. Although HoLEP may provide more durable improvement of VS in men with DU than HPS, there seems to be no difference in improvement of QOL or Qmax or BVE between HPS and HoLEP.