Advances in the Management of Post-Radical Prostatectomy Erectile Dysfunction: Treatment Strategies When PDE-5 Inhibitors Don't Work

Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of post-radical prostatectomy erectile dysfunction. For those patients who undergo a non-nerve-sparing radical prostatectomy or whose condition fails to respond to PDE-5 inhibitors, alternative treatment with intracavernous injection therapy, transurethral alprostadil, vacuum erection devices, and recently described combination therapy is available. The goals of therapy are to provide the patient with a means of obtaining an erection so that the patient and his partner may resume sexual relations as soon as possible following radical prostatectomy. There is evidence that early institution of treatment may promote improvement in the return of spontaneous erections in patients who have undergone nerve preservation. In patients who undergo non-nerve-sparing procedures, therapy may improve penile rigidity. Intracavernous injection therapy, transurethral alprostadil, and vacuum devices are highly effective in the management of post-prostatectomy erectile dysfunction. High dropout rates, which are not related to adverse effects, have been described with all 3 modalities. Pre- and postoperative counseling may improve patient and partner satisfaction.     

The Use of Exome Genotyping to Predict Pathological Gleason Score Upgrade after Radical Prostatectomy in Low-Risk Prostate Cancer Patients

Background

Active surveillance (AS) is a promising option for patients with low-risk prostate cancer (PCa), however current criteria could not select the patients correctly, many patients who fulfilled recent AS criteria experienced pathological Gleason score upgrade (PGU) after radical prostatectomy (RP). In this study, we aimed to develop an accurate model for predicting PGU among low-risk PCa patients by using exome genotyping.

Methods

We genotyped 242,221 single nucleotide polymorphisms (SNP)s on a custom HumanExome BeadChip v1.0 (Illuminam Inc.) in blood DNA from 257 low risk PCa patients (PSA <10 ng/ml, biopsy Gleason score (GS) ≤6 and clinical stage ≤T2a) who underwent radical prostatectomy. Genetic data were analyzed using an unconditional logistic regression to calculate an odds ratio as an estimate of relative risk of PGU, which defined pathologic GS above 7. Among them, we selected persistent SNPs after multiple testing using FDR method, and we compared accuracies from the multivariate logistic model incorporating clinical factors between included and excluded selected SNP information.

Results

After analysis of exome genotyping, 15 SNPs were significant to predict PGU in low risk PCa patients. Among them, one SNP – rs33999879 remained significant after multiple testing. When a multivariate model incorporating factors in Epstein definition – PSA density, biopsy GS, positive core number, tumor per core ratio and age was devised for the prediction of PGU, the predictive accuracy of the multivariate model was 78.4% (95%CI: 0.726–0.834). By addition the factor of rs33999879 in aforementioned multivariate model, the predictive accuracy was 82.9%, which was significantly increased (p = 0.0196).

Conclusion

The rs33999879 SNP is a predictor for PGU. The addition of genetic information from the exome sequencing effectively enhanced the predictive accuracy of the multivariate model to establish suitable active surveillance criteria.     

彩色多普勒超声在血管性勃起功能障碍中的诊断价值

目的:研究彩色多普勒超声(CDDS)在血管性勃起功能障碍(ED)中的诊断价值,从而为患者临床诊断方式的选择提供参考。方法:选择本院内2012年4月至2015年3月期间因ED入院接受治疗的男性患者248例,在患者接受检查前,需将酚妥拉明、罂粟碱以及前列腺素-E1等药物混合液0.2 m L注入阴茎海绵体内,使得诱导阴茎勃起,随后使用彩色多普勒超声系统进行诊断,对阴茎海绵体动脉的收缩期最大血流率(PSV)、舒张末期血流率(EDV)、阻力指数(RI)等指标进行记录,对各指标诊断ED的应用价值进行评估。结果:在248例患者中,存在血流动力学异常病例172例,其中96例患者为动脉性ED,72例患者为静脉性ED;72例血流动力学正常病例,为非血管性ED。合并糖尿病25例,占10.08%;高血压17例,占6.85%;高血脂116例,占46.77%;阴茎硬结症7例,占2.82%;阴茎海绵体纤维化8例,占3.23;经腹前列腺切除术后者9例,占3.2%,经尿道切除前列腺术后者8例,占3.23;吸烟者196例,占79.03%。血管性ED患者的FPSV、PSV、EDV明显低于非血管性ED患者的,差异均有统计学意义(P0.05);且在血管性ED患者中,动脉性FPSV、ED、EDV患者的PSV明显低于非血管性ED患者的,差异均有统计学意义(P0.05)。在指标对比中,血管性ED患者的RI与非血管性ED患者的RI无明显差异(P0.05),但静脉性ED患者的RI明显低于非血管性ED患者的,差异均有统计学意义(P0.05)。在96例动脉性ED患者中,行选择性阴部内动脉造影术有11例,动脉性病变8例,彩色超声多普勒检查与选择性阴部内动脉造影术符合率为72.73%。结论:在诱导阴茎勃起后,对患者进行彩色多普勒超声系统诊断,能够有效排除阴茎在疲软状态下存在的可变性因素,能够准确反映阴茎血流动力学状态,从而能够准确筛查血管性ED疾病,其检测结果的准确性优于动脉造影,临床应用价值较高,值得进一步推广使用。     

Systems for Maintenance of Urinary Sterility After Prostatectomy

Closed drainage is recommended for all patients after prostatectomy where hemostasis has been adequate. Although closed drainage can maintain sterility of the bladder, thereby fostering healing and reducing infectious complications, such drainage is not insisted upon at most hospitals because of the inconveniences associated with it. However, when closed drainage was used in 25 consecutive cases of transurethral resection, infection was reduced to 25 per cent (in contrast to the 85 to 100 per cent encountered with open drainage).The ideal closed system should incorporate:1. Fixed tubing to prevent contamination where the catheter joins the tubing and where the tubing is attached to the container;2. An aseptic method of emptying;3. A device to prevent reflux of the potentially contaminated urine in the container into the bladder;4. Free urinary flow from bladder to container; and5. Portability for the patient and convenience for the staff.A system is proposed that incorporates these features. Particularly effective are a fixed drip chamber with vents at the site of attachment of the tubing to the bag and a protected spigot for emptying.     

Salvage Radiotherapy after Radical Prostatectomy: Prediction of Biochemical Outcomes

Introduction

A significant proportion of patients undergoing salvage radiotherapy (RT) for biochemical recurrence (BCR) following radical prostatectomy (RP) may again experience BCR after salvage RT. Thus, we evaluated the clinical significances of different parameters on the biochemical outcome of RT in salvage setting.

Methods

We reviewed the records of 212 patients who underwent salvage RT between November 2003 and December 2012 for BCR following primary RP. BCR-free survivals after salvage RT were estimated using the Kaplan–Meier method. Cox proportional hazard regression models were used to evaluate the impacts of clinicopathologic parameters on BCR following salvage RT.

Results

The overall median follow-up duration was 63.5 months. The BCR-free survival rate after salvage RT was 58.2% at 5 years. Multivariate analysis showed that a pre-RT prostate-specific antigen (PSA) level of ≤0.5 ng/mL, a pre-RT PSA doubling time (PSADT) of >4.5 months, concomitant androgen deprivation therapy (ADT) with salvage RT, and a positive surgical margin were independent predictors of favorable biochemical outcomes after salvage RT (hazard ratios [HR] = 3.012, 1.132, 2.000, and 1.805, respectively, p = less than 0.001, 0.013, 0.005, and 0.036, respectively). In the early (pre-RT PSA ≤0.5 ng/mL) salvage RT setting, concomitant ADT administration was also shown to be significantly associated with higher risk of BCR-free survival following salvage RT (HR = 2.611, p = 0.038).

Conclusion

Lower pre-RT PSA value, longer PSADT before salvage RT, concomitant ADT administration, and a positive surgical margin were significant predictors of favorable biochemical outcomes following salvage RT performed for BCR after primary RP.     

前列腺癌根治性切除术后会阴部红外线照射提高患者控尿的 前瞻性的研究

目的:探讨对于前列腺癌根治术的患者,术后采用红外线会阴部照射,提高患者拔管后控尿的效果。方法:对76例前列腺癌根治术后患者,随机分为两组,实验组术后第一天起采用会阴部红外线照射治疗,连续10天,空白对照组不做任何处理,然后评估患者拔除尿管后控尿情况。结果:随访一年后发现,实验组中,37(97%)例的患者能够控制排尿,而对照组31(82%)例患者能够控制排尿(P=0.01)。实验组中可以控制排尿的患者,在拔除尿管以后,平均25±39天后可以控制排尿;而对照组中的患者则需要75±103天才能控制排尿(P<0.001)。接受红外线照射的患者尿控情况明显好于未接受治疗患者。结论:盆底红外线照射是前列腺癌根治术后提高患者尿控能力的有效的治疗方式。     

Management of Erectile Dysfunction in the Hypogonadal Man: A Case-Based Review

Erectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. ED often precedes coronary artery disease in half of affected subjects, and could indicate the presence of cardiovascular pathology. The pathophysiology and role of androgens in sexual function are described, along with the relevant literature on the effects of aging in erectile and gonadal function. The concept of testosterone supplementation (TST) in men with ED is reviewed. The authors utilize clinical vignettes to discuss the appropriate management of two clinical cases of men at different life stages who have ED in the setting of hypogonadism and propose a treatment algorithm. In patients of all ages, proper identification of the underlying pathophysiology of decreased libido and erectile function is paramount in choosing between the use of TST, phosphodiesterase type 5 inhibitors, or both, in the management of these disorders.Key words: Erectile dysfunction, Testosterone supplementation, Hypogonadism, Phosphodiesterase type 5 inhibitorsErectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. Because ED often precedes coronary artery disease (CAD) in half of affected subjects, it may be considered a harbinger of indolent cardiovascular pathology.^1,2 The modulation of erectile function by testosterone is well known,^3,4 and in men with both hypogonadism and ED a treatment strategy necessitating management of both conditions is required.Phosphodiesterase type 5 inhibitors (PDE5i) and testosterone supplementation therapy (TST) are established treatment strategies for ED and hypogonadism, respectively. Using a PDE5i in combination with TST has the potential for improving efficacy in men with concurrent ED and hypogonadism compared with the use of either agent alone. However, in light of the recent evidence associating testosterone with cardiovascular risk in elderly men,^5,6 TST should be used judiciously in the management of ED in older men.     

Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis

IntroductionStem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED). Many relative animal studies have been done to evaluate the efficacy of this therapy in rats.AimsThis meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED.MethodsWe searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and in the structure of the cavernous body were compared.Results10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001). In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF). Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification.ConclusionsOur results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic strategy for diabetic ED.     

维药罗补甫克比日丸对DM性勃起功能障碍大鼠性激素水平的影响

目的:揭示维药罗补甫克比日丸对糖尿病(DM)性勃起功能障碍(ED)大鼠性激素水平的影响。方法:取50只SD雄性大鼠,从中随机取7只设为正常对照(A)组,余43只行腹腔注射链尿佐菌素(STZ)制造DM动物模型,未成模者为STZ组,成模者用阿朴吗啡(APO)筛选DM性ED模型,并将其随机分为DM性ED对照组、药罗补甫克比日丸(C)组、胰岛素(D)组、联用(E)组,未成ED模者为DM(F)组,共7组。药物干预6周后,检测外周血中性激素水平。结果:正常对照(A)组、DM性ED胰岛素(D)组、DM性ED联用(E)组、STZ(G)组睾酮(T)水平显著高于DM性ED对照(B)组、DM性ED伊木萨克(C)组、DM(F)组,有显著性差异(P0.01);正常对照(A)组、STZ(G)组促黄体生成激素(LH)水平显著低于DM性ED伊木萨克(C)组、DM性ED联用(E)组,有显著性差异(P0.05、P0.01);DM性ED对照(B)组、DM性ED补甫克比日丸(C)组促卵泡刺激素(FSH)水平显著低于DM性ED胰岛素(D)组、DM性ED联用(E)组,有显著性差异(P0.01、P0.05)。结论:维药罗补甫克比日丸可显著改善DM性ED大鼠睾酮水平,且与胰岛素联用优于单用,维药罗补甫克比日丸治疗DM性ED的作用机制可能与T、LH、FSH含量变化有关。     

Erectile Dysfunction and Cardiovascular Events in Diabetic Men: A Meta-analysis of Observational Studies

Background

Several studies have shown that erectile dysfunction (ED) influences the risk of cardiovascular events (CV events). However, a meta-analysis of the overall risk of CV events associated with ED in patients with diabetes has not been performed.

Methodology/Principal Findings

We searched MEDLINE and the Cochrane Library for pertinent articles (including references) published between 1951 and April 22, 2012. English language reports of original observational cohort studies and cross-sectional studies were included. Pooled effect estimates were obtained by random effects meta-analysis.A total of 3,791 CV events were reported in 3 cohort studies and 9 cross-sectional studies (covering 22,586 subjects). Across the cohort studies, the overall odds ratio (OR) of diabetic men with ED versus those without ED was 1.74 (95% confidence interval [CI]: 1.34–2.27; P<0.001) for CV events and 1.72 (95% CI: 1.5–1.98; P<0.001) for coronary heart disease (CHD). The funnel plot, Begg''s test, and Egger''s test did not show evidence of publication bias (all P>0.05). Moreover, meta-regression analysis found no relationship between the method used to assess ED (questionnaire or interview), mean age, mean hemoglobin A_1c, mean body mass index, or mean duration of diabetes and the risk of CV events or CHD. In the cross-sectional studies, the OR of diabetic men with ED versus those without ED was 3.39 (95% CI: 2.58–4.44; P<0.001) for CV events (N = 9), 3.43 (95% CI: 2.46–4.77; P<0.001) for CHD (N = 7), and 2.63 (95% CI: 1.41–4.91; P = 0.002) for peripheral vascular disease (N = 5).

Conclusion/Significance

ED was associated with an increased risk of CV events in diabetic patients. Prevention and early detection of cardiovascular disease are important in the management of diabetes, especially in view of the rapid increase in its prevalence.     

Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO₂ permeability was also excellent for compound 18 .     

可膨胀阴茎支撑体植入术治疗勃起功能障碍的临床应用及分析

目的:探讨可膨胀阴茎支撑体植入术治愈男性勃起障碍(ED)的可靠性,了解阴茎支撑体植入术的临床效果,使患者生理与心理的疾病得到有效治疗.方法:使用国产三件套可膨胀阴茎支撑体治疗器质性ED患者,并对21例患者的临床资料进行回顾性分析.结果:手术过程顺利,术后未发生感染,未见机械性并发症;随访中有两例因情绪紧张,自感性交欠满意,其余19例均性交满意.结论:阴茎支撑体植入术治疗难治性ED疗效满意,机械性能安全、可靠,该方法具有临床治疗与实践应用的可行性.     

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

Association Between Financial Conflicts of Interests and Supportive Opinions for Erectile Dysfunction Treatment

A conflict of interest (COI) is a situation in which a person has competing loyalties or interests that make it difficult to fulfil his or her duties impartially. Conflict of interest is not categorically improper in itself but requires proper management. A SCOPUS literature search was performed for publications on the efficacy/safety of Phospho-Di-Esterase Inhibitors (PDEIs) for treating erectile dysfunction. A categorization tool (CoOpCaT) was used to review and classify the publications as supportive/not-supportive for the discussed active ingredient and reporting or not reporting a COI for that specific drug or for the remaining PDEIs (i.e. competitors). Multivariable binary logistic regression was performed. In the 419 selected records the prevalence of supportive opinions was higher when a COI for the index label was declared. The CoOpCaT showed good internal consistency, discriminative validity and intra/inter-rater agreement. The strongest predictor for a supportive opinion was the total number of financial COIs for the index label. A mild protective effect of the total number of financial COIs for any competitor label was noted. Financial COIs have frequently been associated with bias, and the measures currently adopted to restrain it lack effectiveness. Some evidence for monitoring and/or compensating this bias is reported here, but the ultimate solution remains distant.     

The Unexpected Evolution of Basic Science Studies about Cyclic Nucleotide Action into a Treatment for Erectile Dysfunction

In these Reflections, I describe my perceived role in discoveries made in the cyclic nucleotide field that culminated in the advent of PDE5 inhibitors that treat erectile dysfunction, such as Viagra, Levitra, and Cialis. The discoveries emphasize the critical role of basic science, which often evolves in unpredictable and circuitous paths, in improving human health.