Erectile dysfunction and diabetes mellitus

Background: Erectile dysfunction (ED) is highly prevalent, affecting ≥50% of men with diabetes mellitus (DM) worldwide.Objective: This article reviews current knowledge on the epidemiology and underlying pathophysiology of ED in men with DM, diagnostic modalities, and treatment options.Methods: A MEDLINE literature search was conducted for articles published in English from inception of the database through November 2008, using the terms erectile dysfunction, diabetes, epidemiology, pathophysiology, phosphodiesterase inhibitors, intracavernosal injection, and penile prosthesis. Data on the epidemiology, diagnosis, and treatment of ED were extracted from all relevant articles.Results: The literature search revealed 685 original articles and reviews, 67 of which were selected for inclusion in this review. DM may cause ED through a number of pathophysiologic changes, including neuropathy, endothe-lial dysfunction, cavernosal smooth muscle structural/functional changes, hormonal changes, and psychological effects. The diagnosis of ED in men with DM is based on their sexual and medical histories and results of validated questionnaires such as the International Index of Erectile Function. Laboratory examinations are usually limited to testosterone and prolactin levels that may independently contribute to ED because specialized examinations are not necessary in most diabetic men with ED. The first step in the treatment of ED in men with DM includes glycemic control and treatment of diabetic comorbidities. The associated hypogonadism must also be treated; otherwise, pharmacologic treatment may be less efficacious or not efficacious at all. Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of ED, and they are considered first-line treatment, with a mean efficacy rate of 50% and a favorable safety profile. Intracavernous administration of vasoactive drugs is the second-line medical treatment when PDE-5 inhibitors have failed. Alprostadil is the most widely used drug for this condition, but the combination of papaverine, phentolamine, and alprostadil represents the most efficacious pharmacologic treatment option for patients whose ED does not respond to monotherapy. Excellent functional and safety results have been reported for penile prosthesis implantation, and this approach, along with proper counseling, can be considered for selected patients with treatment-refractory ED.Conclusions: ED is common in men with DM, who represent one of the most difficult-to-treat subgroups of ED patients. PDE-5 inhibitors are the first-line treatment option, followed by intracavernosal injections and implantation of a penile prosthesis.     

Stem cell therapy and diabetic erectile dysfunction: A critical review

Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.     

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.     

Virtual Screening and Drug Design for PDE-5 Receptor from Traditional Chinese Medicine Database

Abstract

Erectile dysfunction (ED) is a sexual disorder mainly caused by decrease in cellular concentration of cyclic guanosine monophosphate (cGMP), which is degraded by phosphodiesterase type-5 (PDE-5). As a potent therapeutic target, inhibitors such as Viagra®, Cialis®, and Levitra® have already been developed to target PDE-5 for treating ED; traditional Chinese medicine, Epimedium sagittatum, also has shown prominent results as well. To developed new PDE-5 inhibitors, we performed a virtual screening of traditional Chinese medicine (TCM) database and docking analyses to identify candidates. Known PDE-5 inhibitors were used to construct a three dimensional quantitative structure-activity relationship (3D QSAR) model by HypoGen program. From docking analyses, isochlorogenic acid b was identified as the most potential inhibitory compound. De novo evolution designed 47 derivatives. Of the 47 derivatives, seven were able to map into the pharmacophore model, and these seven compounds were suggested to be the most promising leads for inhibiting PDE-5. An analysis of the hydrogen bond interactions formed between the docked ligands and PDE-5 identified ASN662, SER663 and GLN817 as the most frequently interacting residues. A total of eight novel leading compounds were identified to have favorable interaction with PDE-5. These compounds all had hydrogen bond interactions with three key residues that could be further investigated for understanding of PDE-5 and ligands interaction.     

Lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction, and phosphodiesterase-5 inhibitors

Many patients who present to their healthcare provider with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) will also have erectile dysfunction (ED), and vice versa. Although alpha-adrenergic receptor blockers and 5-alpha-reductase inhibitors are highly effective in treating BPH-associated LUTS, these agents have sexual adverse effects that cause many men to discontinue therapy. The discovery of nitric oxide as a major factor in the mechanism of erection has led to the development of new drugs for ED, including the phosphodiesterase (PDE) inhibitors. Preliminary data support the theory that inhibition of PDE isoenzymes in the prostate may improve LUTS due to BPH through relaxation of prostatic smooth muscle. Further studies of PDE inhibitors in men with ED and BPH-associated LUTS are indicated.     

Use of phosphodiesterase-5 inhibitors and the incidence of melanoma

IntroductionRecent evidence of a causal link between Phosphodiesterase-5-inhibitor (PDE-5i) use and melanoma has caused concern in PDE-5i use and was even addressed in the 2018 American Urological Association guideline on erectile dysfunction (ED). Given that several studies have affirmed this low probability but statistically significant association, one might expect a shift in melanoma diagnoses since PDE-5is were introduced in 1998. We sought to determine if the introduction of PDE-5i drugs for ED treatment increased incidence of melanoma.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to compare the incidence of melanoma diagnosis in American men between 1973 and 2015, providing over a decade of data before and after PDE-5i introduction in 1998. Interrupted time-series and logistic regression were used to assess this relationship.ResultsOver 43 years, the SEER database has reported 292,166 cases of Melanoma, with males accounting for 53.7% of cases (Standard deviation [SD] 3%, Range 47.5–58.3%). After the introduction of PDE-5i, there was no proportional increase in melanoma diagnoses, in fact demonstrating a 2% lower incidence from prediction models (p < 0.05).ConclusionOur analysis of the SEER database demonstrates that the trend in incidence of melanoma has fallen in the era of PDE-5i use for ED. These findings may be of value in counseling patients anxious about the potential association between PDE-5i use and skin cancer; however, continued research analyzing individual-level risk are needed.     

Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF

Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.     

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial

Background aimsThe efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM.MethodsTen patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function.ResultsOf the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222).ConclusionsThis phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors’ results need to be confirmed by a phase 2 clinical trial.     

MIA-QSAR,PCA-ranking and least-squares support-vector machines in the accurate prediction of the activities of phosphodiesterase type 5 (PDE-5) inhibitors

Phosphodiesterase type-5 (PDE-5) is a key enzyme involved in the erection process. PDE-5 inhibitors, such as Sildenafil (Viagra^TM), Vardenafil (Levitra^TM) and Tadalafil (Cialis^TM), are used for the treatment of erectile dysfunction. Computer-assisted modelling of biological activities of PDE-5 inhibitors may make quantitative structure–activity relationship (QSAR) models useful for the development of safer (low side effects) and more potent drugs. The multivariate image analysis applied to QSAR (MIA-QSAR) method, coupled to partial least-squares (PLS) regression, has provided highly predictive QSAR models. Nevertheless, regression methods which take into account nonlinearity, such as least-squares support-vector machines (LS-SVMs), are supposed to predict biological activities more accurately than the usual linear methods. Thus, together with prior variable selection using principal component analysis ranking, MIA-QSAR and LS-SVM regression were applied to model the bioactivities of a series of cyclic guanine derivatives (PDE-5 inhibitors), and the results were compared with those based on linear methodologies. MIA-QSAR/LS-SVM was found to improve greatly the prediction performance when compared with MIA-QSAR/PLS, MIA-QSAR/N-PLS, CoMFA/PLS and CoMSIA/PLS models.     

Diabetes,obesity, and erectile dysfunction

Background: Diabetes mellitus (DM) and obesity affect large parts of the population in the United States and around the world. These disorders are among the most common risk factors for erectile dysfunction (ED), because of their effects on the vasculature and the hormonal milieu.Objective: This article reviews the current literature on the connection between DM, obesity, and ED.Methods: Using the search terms erectile dysfunction, endothelial dysfunction, hypogonadism, diabetes, and obesity, a systematic review of the available literature in the PubMed database was conducted. Relevant English-language publications (to August 2008) were identified.Results: ED is highly prevalent in men with both DM and obesity, and may act as a harbinger for cardiovascular disease (CVD) in this high-risk population. In addition to male hypogonadism and macrovascular disease, endothelial dysfunction is central to the connection between the metabolic syndrome and ED. Conversely, improved glycemic control and weight loss have been found to improve erectile function.Conclusion: ED is very prevalent in men with DM and obesity. It is increasingly being recognized as an early clinical indicator and motivator for patients with CVD. The role of pharmacologic ED treatments in improving endothelial function is currently being investigated.     

The Use of Vacuum Erection Devices in Erectile Dysfunction After Radical Prostatectomy

The risk of postoperative erectile dysfunction (ED) following radical prostatectomy (RP) is reported to be between 14% and 89%. With an increase in the detection of prostate cancer in younger men, there is a greater emphasis on the appropriate management of ED following RP. A number of options are available to manage ED after RP, including phosphodiesterase-5 inhibitors, intracorporeal injections, intraurethral alprostadil, and vacuum erection devices (VEDs). Penile rehabilitation programs are increasingly used to facilitate the return of natural postoperative erections; the VED is an ideal therapy given that it increases blood flow and oxygenation to the corpora to reverse the changes that result in ED after RP.Key words: Erectile dysfunction, Radical prostatectomy, Vacuum erection device, Penile rehabilitationProstate cancer is the most common cancer in men over the age of 50 years.¹ When patients undergo a radical prostatectomy (RP), there is a risk of postoperative erectile dysfunction (ED). The incidence of ED following RP has been reported to be between 14% and 89%.² With an increase in the detection of prostate cancer in younger men, there is a greater emphasis on the appropriate management of ED after RP. With an early diagnosis of prostate cancer, there is an increase in the rate of RP in younger men and the importance of ED as a quality-of-life issue has subsequently increased.² There are a number of options available to manage ED after RP, including phosphodiesterase-5 (PDE-5) inhibitors, intracorporeal injections, intraurethral alprostadil, and vacuum erection devices (VEDs). Despite highly reported satisfaction and efficacy with VEDs, there is a move by some medical practitioners away from VEDs due to cost. But what evidence is there for VED success after prostatectomy and what role do VEDs have in penile rehabilitation after ED? We present current evidence and provide our recommendations based on the latest literature.     

Efficacy of a cultured conditioned medium of exfoliated deciduous dental pulp stem cells in erectile dysfunction patients

Majority of current treatment strategies against erectile dysfunction (ED) has been consisted of only a supportive care to sustain enough erection during a sexual intercourse. In this study, we investigated whether the cultured conditioned medium of human exfoliated deciduous dental pulp stem cells (SHED‐CM) had an ability to treat ED through fundamentally repairing the pathological damage of vascular endothelial cells of the corpus cavernosum. An open‐label pilot study was performed from April 2016 to October 2020. SHED‐CM was injected directly into the corpus cavernosum of penis of 38 ED patients who visited our clinic and fulfilled the inclusion criteria. Efficacy was assessed using the simplified International Index of Erectile Function (IIEF‐5) questionnaire. The average age and initial IIEF‐5 score of the patients enrolled in this study was 56 (31–79) years old and 13.1 (5–20) points, respectively. Medical history revealed 7 patients with diabetes, 7 patients with hypertension and 1 patient with priapism undergone shunt operation. Of these, 37 patients (97.4%) showed an improvement in IIEF‐5 of an average of 19.3 (7–25) points or 64.4 (10–300) % increase after three injections of SHED‐CM. Eighteen patients (47.4%) achieved more than 21 points (no ED) in IIEF‐5. No adverse events were encountered. This is the first clinical report of ED treatment in the literatures evaluating the efficacy of SHED‐CM. Treatment with SHED‐CM is expected to repair vascular damages of the corpus cavernosum, which are the main cause of ED, and to be widely spread as a fundamental clinical application for ED.     

Key features for designing phosphodiesterase-5 inhibitors

Phosphodiesterase superfamily is the key regulator of 3',5'-cyclic guanosine monophosphate (cGMP) decomposition in human body. Phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, vardenafil and tadalafil, are well known oral treatment for males with erectile dysfunction. To investigate the inhibitory effects of traditional Chinese medicine (TCM) compounds to PDE-5, we performed both ligand-based and structure-based studies on this topic. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted to construct three dimensional quantitative structure-activity relationship (3D-QSAR) models of series of known PDE-5 inhibitors. The predictive models had cross-validated, q(2), and non cross-validated coefficient, r(2), values of 0.791 and 0.948 for CoMFA and 0.724 and 0.908 for CoMSIA. These two 3D-QSAR models were used to predict activity of TCM compounds. Docking simulations were performed to further analyze the binding mode of training set and TCM compounds. A putative binding model was proposed based on CoMFA and CoMSIA contour maps and docking simulations; formation of pi-stacking, water bridge and specific hydrogen bonding were deemed important interactions between ligands and PDE-5. Of our TCM compounds, engeletin, satisfied our binding model, and hence, emerged as PDE-5 inhibitor candidate. Using this study as an example, we demonstrated that docking should be conducted for qualitative purposes, such as identifying protein characteristics, rather than for quantitative analyses that rank compound efficacy based on results of scoring functions. Prediction of compound activity should be reserved for QSAR analyses, and scoring functions and docking scores should be used for preliminary screening of TCM database (http://tcm.cmu.edu.tw/index.php).     

Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorate erectile dysfunction via lipocalin 2 in diabetic mice

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Men with diabetic ED do not respond well to oral phosphodiesterase-5 inhibitors owing to neurovascular dysfunction. Pericyte-derived extracellular vesicle-mimetic nanovesicles (PC-NVs) are known to promote nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs effectively promoted penile angiogenesis and neural regeneration under diabetic conditions, thereby improving erectile function. Specifically, PC-NVs induced endothelial proliferation and migration and reduced cell apoptosis under diabetic conditions. In addition, PC-NVs induced neural regeneration in STZ-induced diabetic mice in dorsal root ganglion and major pelvic ganglion explants in vivo and ex vivo under high-glucose conditions. We found that lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, demonstrating that PC-NVs exert their angiogenic and nerve-regeneration effects by activating MAP kinase and PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner. Our findings provide new conclusive evidence that PC-NVs can promote neurovascular regeneration and recovery of erectile function under diabetic conditions via an Lcn2-dependent mechanism. Thus, local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED.     

A photoaffinity probe covalently modifies the catalytic site of the cGMP-binding cGMP-specific phosphodiesterase (PDE-5)

The cGMP-binding cGMP-specific phosphodiesterase (PDE-5) contains distinct catalytic and allosteric binding sites, and each is cGMP-specific. Cyclic nucleotide phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX), are believed to compete with cyclic nucleotides at the catalytic sites of these enzymes, but the portion of PDE-5 that accounts for interaction of either of these inhibitors or the substrates themselves with the catalytic domain of the enzymes has not been identified. IBMX was derivatized to yield the photoaffinity probe 8([3-¹²⁵I,-4-azido]-benzyl)-IBMX, which is referred to as 8(¹²⁵IAB)-IBMX. This probe was incubated with partially purified recombinant bovine PDE-5. After UV irradiation and SDS-PAGE, a single radiolabeled band that coincided with the position of PDE-5 was visualized on the gel, and the photoaffinity labeling of PDE-5 was linear with increasing concentration of the 8(¹²⁵IAB)-IBMX. Prominent Coomassie blue-stained bands other than PDE-5 were not labeled significantly. The photo-affinity labeling was progressively blocked by cGMP at concentrations higher than 10 μM, whereas cAMP or 5′-GMP exhibited only weak inhibitory effects. Other compounds that are believed to interact with the PDE-5 catalytic site, including IBMX, clMP, and β-phenyl-1,N ²-etheno-cGMP (PET-cGMP), also inhibited the photoaffinity labeling in a concentration-dependent manner. The IC₅₀ of PET-cGMP for inhibition of photoaffinity labeling was 10 μM, which compared favorably with an IC₅₀ of 5 μM for inhibition of PDE-5 catalytic activity by this compound. It is concluded that the interaction of this photoaffinity probe with PDE-5 is highly specific for the catalytic site over the allosteric binding sites of PDE-5 and could prove useful in studies to map the catalytic site of PDE-5.     

La dysfonction érectile, un marqueur précoce d’atteinte cardio-vasculaire

Erectile dysfunction (ED) affects approximately 100 million men in the world and 50% of men between the ages of 40 and 70 years. The commonest cause is a vascular disorder of penile arteries. ED may therefore be a an early marker of cardiovascular disease (CVD). The main arguments in favour of this assertion are primarily epidemiological, but also pathophysiological, as control of cardiovascular risk factors such as smoking, obesity and hypertension may prevent not only CVD, but also ED. This relationship is particularly strong in diabetic patients, in whom ED can be considered to be an element able to identify patients at risk of asymptomatic heart disease. From a pathophysiological point of view, small calibre penile vessels present signs of obstruction earlier than larger vessels because they are more sensitive to even minor haemodynamic changes. There is also a significant correlation between the severity of ED and the number of vessels affected in patients with coronary artery disease. Endothelial dysfunction is the common denominator underlying these diseases and therefore represents a major cause of ED. Preliminary studies have shown that PDE-5 inhibitors can reduce symptoms, improve exercise tolerance, and reduce endothelial dysfunction in patients after cardiac arrest and in diabetics. In the years to come, ED may therefore be added to the classical cardiovascular risk factors and could characterize a population with an increased risk of coronary artery disease.     

Oral and non-oral combination therapy for erectile dysfunction

An estimated 30 million men in the United States suffer from varying degrees of erectile dysfunction. Increasing age and comorbidities are likely to increase the number of men who are initially refractory or become refractory to phosphodiesterase (PDE)-5 inhibitors, the most popular oral therapy. Combination therapy, a concept well proved in other areas of medicine, is therefore of increasing importance. Combination oral and non-oral (intracavernosal injection and intraurethral application) therapies have been shown to salvage monotherapy. The early introduction of combination therapy has been shown to expedite both the return of natural function and PDE-5 inhibitor responsiveness in post-prostatectomy patients with no reports of serious adverse events. Larger controlled studies are needed to corroborate those encouraging findings.     

Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction

Abstract

Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). Numerous studies have investigated the role of the AGEs in cardiovascular system; however, its contribution to erectile dysfunction (ED) that is an early manifestation of cardiovascular disease has been less intensively investigated. This review summarizes the most recent advances concerning AGEs effects in the cavernous tissue of the penis and in ED onset, particularly on diabetes and aging, conditions that not only favor AGEs formation, but also increase risk of developing ED. The specific contribution of AGE on intra- and extracellular deposition of insoluble complexes, interference in activity of endothelial nitric oxide (NO) synthase, NO bioavailability, endothelial-dependent vasodilatation, as well as molecular pathways activated by receptor of AGEs are presented. Finally, the interventional actions that prevent AGEs formation, accumulation or activity in the cavernous tissue and that include nutritional pattern modulation, nutraceuticals, exercise, therapeutic strategies (statins, anti-diabetics, inhibitors of phosphodiesterase-5, anti-hypertensive drugs) and inhibitors of AGEs formation and crosslink breakers, are discussed. From this review, we conclude that despite the experiments conducted in animal models pointing to the AGE/RAGE axis as a potential interventional target with respect to ED associated with diabetes and aging, the clinical data have been very disappointing and, until now, did not provide evidence of benefits of treatments directed to AGE inactivation.     

Les inhibiteurs de la phosphodiestérase de type 5 : une révolution dans le traitement des sympt?mes du bas appareil urinaire?

Context

The incidence of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) increases with age, affecting 50% of patients aged over 50 years and 90% of those aged over 80 years. The prevalence and severity of erectile dysfunction (ED) also increase with age. Its prevalence is estimated to be 31.6% in men over 40 years. LUTS as well as ED significantly affect the quality of life of patients and their partners. Several studies have shown that LUTS represent an independent risk factor for ED. The severity of LUTS is correlated with that of ED. The pathophysiological hypothesis linking LUTS to ED are an increase in sympathetic tone, alteration of NO/cGMP system, alteration of rho kinase system, and pelvic atherosclerosis.

Goal

Some treatments of LUTS have adverse effects on the erectile function. The phosphodiesterase type 5 inhibitors (IPDE 5) revolutionized the treatment of ED.

Material and methods

Several recent clinical studies evaluated the effect of daily treatment by IPDE 5 on LUTS secondary to BPH among patients with or without ED.

Results

This review shows that IPDE 5 administration improves LUTS significantly in 12 randomized clinical trials, as well as in both storage and voiding parts of the international prostate symptom score (IPSS) and in quality of life questionnaire. No adverse events were observed, and ED, which has a high prevalence among this population, was also improved.

Conclusion

The treatment of LUTS by IPDE 5 looks very promising, even though they are not yet approved for this indication in France.