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Diabetes mellitus (DM) is a quite common chronic disease, and the prevalence of erectile dysfunction (ED) is three times higher in this large population. Although diabetes-related ED has been studied extensively, the actin-myosin contractile apparatus was not examined. The mRNAs encoding smooth muscle myosin (SMM) heavy chains (MHC) and essential light chains (LC(17)) exist as several different alternatively spliced isoforms with distinct contractile properties. Recently, we provided novel data that blebbistatin (BLEB), a specific myosin II inhibitor, potently relaxed corpus cavernosum smooth muscle (CCSM). In this study, we examine whether diabetes alters SMM expression, alternative splicing, and/or functional activities, including sensitivity to BLEB. By using streptozotocin (STZ)-induced 2-mo diabetic rats, functional activities were tested in vivo by intracavernous pressure (ICP) recording during cavernous nerve stimulation and in vitro via organ bath contractility studies. SMM isoform composition was analyzed by competitive RT-PCR and total SMM, myocardin, and embryonic SMM (SMemb) expression by real-time RT-PCR. Results revealed that the blood glucose level of STZ rats was 407.0 vs. 129.5 mg/dl (control). STZ rats exhibited ED confirmed by significantly increased CCSM contractile response to phenylephrine and decreased ICP response. For STZ rats, SM-B, LC(17a) and SM2 isoforms, total SMM, and myocardin expression increased, whereas SM-A, LC(17b), and SM1 isoforms were decreased, with SMemb unchanged. BLEB was significantly more effective in relaxing STZ CCSM both in vitro and in vivo. Thus we demonstrated a novel diabetes-specific effect on alternative splicing of the SMM heavy chain and essential light chain genes to a SMM isoform composition favoring a heightened contractility and ED. A switch to a more contractile phenotype was supported further by total SMM expression increase. Moreover, the change in CCSM phenotype was associated with an increased sensitivity to BLEB, which may serve as a novel pharmacotherapy for ED.

Erectile dysfunction (ED) is a neurovascular phenomenon modulated by hormonal, local biochemical, and biomechanical/structural factors of the penis. The success of the orally active phosphodiesterase inhibitors for the treatment of ED has boosted research activities into the physiology of the erectile mechanism. Peripheral intracellular signal transduction in the penis as well as central brain and spinal cord pathways controlling penile erection have been investigated and are now better understood. The results of this ongoing research have provided the basis for the development and introduction of several novel therapeutic modalities into the management of ED. Many novel pharmacotherapeutic approaches under development including the use of melanocortins and Rho-kinase inhibitors as well as the introduction of gene therapy and tissue engineering have demonstrated efficacy in animal as well as early human trials. This review describes the major new and evolving pharmacological advances in the field of oral pharmacotherapy for the treatment of male ED., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Gene transfer for the treatment of erectile dysfunction has completed phase 1 safety testing and has shown the necessary safety to proceed to the next level of clinical trial. This review focuses on the background of the components of that have led to US Food and Drug Administration acceptance of human gene transfer trials for nonlethal disease.

Introduction: Clinical trials in male sexual dysfunction (MSD) are expanding. Consequently, there is a need for consensus standards in this area., Aim: To develop an evidence-based, state-of-the-art consensus report on standards for clinical trials in MSD., Methods: A literature review was performed examining clinical trials in erectile dysfunction (ED), premature ejaculation (PE), delayed/absent ejaculation, libido disorders/loss of desire, hypogonadism, and Peyronie's disease, focusing on publications published in the last 20 years. This manuscript represents the opinions of eight experts from seven countries developed in a consensus process. This document was presented for peer review and debate in a public forum and revisions were made based on recommendations of chairpersons to the International Consultation on Sexual Medicine., Main Outcome Measure: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate., Results: According to experience and recent publications in dealing with clinical trials in sexual dysfunction, recommendations have been made for conducting trials in patients with ED, PE, delayed ejaculation, libido disorders, hypogonadism, and Peyronie's disease., Conclusions: It is important that future clinical trials are conducted using standards upon which investigators can rely when reading manuscripts or conducting new trials in this field.

Background: Despite the advent of effective oral therapies for erectile dysfunction (ED), many patients are not successfully treated, and side effects have been documented., Objective: To further evaluate the potential utility of naked DNA-based gene transfer as an attractive treatment option for ED., Design, Setting and Participants: The effects of gene transfer on erectile function and sexual behavior were evaluated in eight male cynomolgus monkeys with ED secondary to moderately severe, diet-induced atherosclerosis., Intervention: Following establishment of baseline characteristics, animals were subjected to intracavernous injection of a smooth-muscle-specific gene transfer vector (pSMAA-hSlo) encoding the pore-forming subunit of the human large-conductance, calcium-sensitive potassium channel (Maxi-K)., Measurements: For the sexual behavior studies, 2 wk of baseline data were obtained, and then animals were placed in the presence of estrogen-implanted females (n=2) three times per week for 30 min, and sexual behavior was recorded. The intracavernous pressure response to papaverine injection was also monitored., Results and Limitations: Dramatic changes in erectile function and sexual behavior were observed after intracorporal gene transfer. The frequency of partial (6±2 to 10±2) and full (2±1.5 to 5±1.4) erections were significantly increased, with a parallel 2-3-fold increase in the duration of the observed erections. The frequency and latency of ejaculation were increased and decreased, respectively. Frequency and duration of grooming by the female were increased, and the latency decreased. Increased latency and decreased frequency of body contact was also observed, and this is characteristic of the typical drop in consort intimacy that occurs after mating in most macaque species. In addition, an increased responsiveness to intracavernous papaverine injection was observed., Conclusions: The data indicate that intracorporal Maxi-K-channel gene transfer enhances erectile capacity and sexual behavior; the data imply that increased erectile function per se may lead to increased sexual function.

Purpose of Review: The purpose of this review is to update the results of the only phase 1 erectile dysfunction gene transfer trial and based upon those results present the outcome of a web-based survey that studied whether or not knowledgeable in the field urologists would use gene transfer in their patients once approved for use by the US Food and Drug Administration., Recent Findings: The results of the clinical trials showed no transfer-related serious adverse events. The response to 10 questions of a web-based survey indicates that gene transfer as a first or second-line therapy for practicing urologists would be well accepted., Summary: Practicing, experienced urologists, after the US Food and Drug Administration approval, are willing to employ gene transfer therapies in their patients, be it men who have failed or dissatisfied with other treatments or as shown in up to one-third of men as a first therapy. That outcome portends for rapid adaptation and active participation into the medical practice for maxi-K or other specific gene transfer, stem cell, or combinations that will be developed in the future.

In the past, many researchers considered viral vectors to be the most promising candidates to transfer genetic material into the corpora for the treatment of erectile dysfunction. However, at present, no viral vectors have progressed to human trials. In contrast, the use of naked gene therapy, a plasmid expressing the human Maxi-K potassium channel, is the only gene therapy treatment to be evaluated in clinical phase I trials to date. The success of these studies, proving the safety of this treatment, has paved the way for the development of future gene transfer techniques based on similar transfer methods, as well as novel treatment vectors, such as stem cell transfer.

Purpose: We identified molecular markers of erectile function, particularly those responding to erectile dysfunction treatment., Materials and Methods: Sprague-Dawley retired breeder rats were intracorporeally injected with pVAX-hSlo, pSMAA-hSlo or the control plasmid pVAX. One week later the intracorporeal pressure-to-blood pressure ratio and gene expression were determined by microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. Rat corporeal cells were transfected in vitro with pVAX-hSlo, pSMAA-hSlo or pVAX and the change in gene expression was determined. We also determined whether Vcsa1 expression was changed after pharmacotherapy using tadalafil., Results: Animals treated with vectors expressing hSlo had significantly improved erectile function compared to that in controls, accompanied by changed expression of a subset of genes. Vcsa1 was one of the genes that was most changed in expression (the third of approximately 31,000 with greater than 10-fold up-regulation). Changes in gene expression were different than those observed in corporeal cells transfected in vitro, distinguishing gene expression changes that were a direct effect of hSlo over expression. When tadalafil was administered in retired breeder rats, the Vcsa1 transcript increased 4-fold in corporeal tissue compared to that in untreated controls., Conclusions: Our study identifies a set of genes that are changed in response to improved erectile function, rather than as a direct effect of treatment. We noted Vcsa1 may act as marker of the restoration of erectile function after gene transfer and pharmacotherapy.

Objective: To determine if ProL1, a member of the opiorphin family of genes, can modulate erectile physiology, as it encodes a peptide which acts as a neutral endopeptidase inhibitor, other examples of which (Vcsa1, hSMR3A) modulate erectile physiology., Materials and Methods: We cloned members of the opiorphin family of genes into the same mammalian expression backbone (pVAX); 100 microg of these plasmids (pVAX-Vcsa1, -hSMR3A, -hSMR3B and -ProL1) were injected intracorporally into retired breeder rats and the affect on erectile physiology assessed visually, by histology and by measuring the intracavernous pressure (ICP) and blood pressure (BP). As a positive control, rats were treated with pVAX-hSlo (expressing the MaxiK potassium channel) and as a negative control the empty backbone plasmid was injected (pVAX). We also compared the level of expression of ProL1 in corporal tissue of patients not reporting erectile dysfunction (ED), ED associated with diabetes and ED not caused by diabetes., Results: Gene transfer of plasmids expressing all members of the opiorphin family had a similar and significant effect on erectile physiology. At the concentration used in these experiments (100 microg) they resulted in higher resting ICP, and histological and visual analysis showed evidence of a priapic-like condition. After electrostimulation of the cavernous nerve, rats had significantly better ICP/BP than the negative control (pVAX). Gene transfer of pVAX-hSlo increased the ICP/BP ratio to a similar extent to the opiorphin homologues, but with no evidence for a priapic-like condition. Corpora cavernosa tissue samples obtained from men with ED, regardless of underlying causes, had significant down-regulation of both hSMR3A and ProL1., Conclusion: All members of the human opiorphin family of genes can potentially modulate erectile physiology. Both hSMR3 and ProL1 are down-regulated in the corpora of men with ED, and therefore both genes can potentially act as markers of ED.

Previous reports have demonstrated that gene transfer with the alpha, or pore-forming, subunit of the human Maxi-K channel (hSlo) restores the decline in erectile capacity observed in established rat models of diabetes and aging. Preliminary data from a human clinical trial also showed safety and potential efficacy in 11 men treated with the same plasmid construct expressing the Maxi-K channel. In all instances, the original plasmid was driven by the heterologous cytomegalovirus promoter which is broadly active in a wide variety of cell and tissue types. To more precisely determine the contribution of the corporal myocyte to the observed physiological effects in vivo, we report here our initial work using a distinct vector (pSMAA-hSlo) in which hSlo gene expression was driven off the mouse smooth muscle alpha-actin (SMAA) promoter. Specifically, older rats, with diminished erectile capacity, were given a single intracorporal injection with either 100 mug pVAX-hSlo or 10, 100 or 1000 mug pSMAA-hSlo, or vector or vehicle alone. Significantly increased intracavernous pressure (ICP) responses to cavernous nerve stimulation were observed for all doses of both plasmids encoding hSlo, relative to control injections. These data confirm and extend previous observations to document that smooth muscle cell-specific expression of hSlo in corporal tissue is both necessary and sufficient to restore erectile function in aging rats.

The potential clinical advantages of a gene transfer therapy-based approach to treatment of genitourinary smooth muscle-based disorders are several: potential single therapy for restoration of normal bladder or erectile function; eliminating the need for daily medication; use in combination with other therapies to reduce dose requirements and side effects; and development of mechanism-based, patient-specific treatment approaches. With the safe administration of hMax-K to men with erectile dysfunction in the first human phase 1 trial and the initiation of the phase 1 trial of hMaxi-K for patients who have detrusor overactivity, we have entered an exciting new era in the development of safe enduring therapies for genitourinary disorders.

Purpose: We recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in 3 distinct models of erectile dysfunction. Since gene transfer of plasmids expressing Vcsa1 or intracorporeal injection of its mature peptide product sialorphin into the corpora of aging rats was shown to restore erectile function, we proposed that the Vcsa1 gene has a direct role in erectile function. To determine if similar changes in gene expression occur in the corpora of human subjects with erectile dysfunction we identified a human homologue of Vcsa1 (hSMR3A) and determined the level of expression of hSMR3A in patients., Materials and Methods: hSMR3A was identified as a homologue of Vcsa1 by searching protein databases for proteins with similarity. hSMR3A cDNA was generated and subcloned into the plasmid pVAX to generate pVAX-hSMR3A. pVAX-hSMR3A (25 or 100 microg) was intracorporeally injected into aging rats. The effect on erectile physiology was compared histologically and by measuring intracorporeal pressure/blood pressure with controls treated with the empty plasmid pVAX. Total RNA was extracted from human corporeal tissue obtained from patients undergoing previously scheduled penile surgery. Patients were grouped according to normal erectile function (3), erectile dysfunction and diabetes (5) and patients without diabetes but with erectile dysfunction (5). Quantitative reverse-transcriptase polymerase chain reaction was used to determine the hSMR3A expression level., Results: Intracorporeal injection of 25 microg pVAX-hSMR3A was able to significantly increase the intracorporeal pressure-to-blood pressure ratio in aging rats compared to age matched controls. Higher amounts (100 microg) of gene transfer of the plasmid caused less of an improvement in the intracorporeal pressure-to-blood pressure ratio compared to controls, although there was histological and visual evidence that the animals were post-priapitic. These physiological effects were similar to previously reported effects of intracorporeal injection of pVAX-Vcsa1 into the corpora of aging rats, establishing hSMR3A as a functional homologue of Vcsa1. More than 10-fold down-regulation in hSMR3A transcript expression was observed in the corpora of patients with vs without erectile dysfunction. In patients with diabetes associated and nondiabetes associated erectile dysfunction hSMR3A expression was found to be down-regulated., Conclusions: These results suggest that hSMR3A can act as a marker for erectile dysfunction associated with diabetic and nondiabetic etiologies. Given that our previous studies demonstrated that gene transfer of the Vcsa1 gene and intracorporeal injection of its protein product in rats can restore erectile function, these results suggest that therapies that increase the hSMR3A gene and product expression could potentially have a positive impact on erectile function.

Background: Ion Channel Innovations has developed a gene transfer product, hMaxi-K, and has begun clinical trials to investigate the effect of increased expression of Maxi-K channels in the smooth muscle of the penis or bladder in patients with erectile dysfunction and those with overactive bladder. The primary function of K channels is to modulate Ca++ influx through Ca-channels (i.e., L-type, voltage-dependent). The amount of Ca++ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction. Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in, for example, penile erection and detrussor muscle relaxation. A phase I clinical trial that used hMaxi-K has been completed and a similar trial to assess safety of the transfer for overactive bladder is about to begin., Objectives: To assess the safety and tolerability of escalating hMaxi-K doses by clinical evaluations and laboratory tests, and to measure efficacy objectives by means of the International Index of Erectile Function scale., Methods: In the erectile dysfunction trial 11 patients with moderate to severe erectile dysfunction were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding for the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel, hSlo. Three patients each were given 500, 1000, and 5000 pg and two patients were given 7500 microg doses of hMaxi-K and followed for 24 weeks. Patient responses were validated by partner responses., Results: There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study., Conclusions: Efficacy conclusions cannot be drawn from results of a phase 1 trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of erectile dysfunction and other smooth muscle diseases with targeted access.

Objective: To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction., Materials and Methods: The RG-U34A rat GeneChip (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing approximately 8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction., Results: In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes., Conclusions: The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.).

The molecular interaction between smooth muscle (SM) myosin and actin in the corpus cavernosum (CC) determines the erectile state of the penis. A key mechanism regulating this interaction and subsequent development and maintenance of force is alternative splicing of SM myosin heavy chain (MHC) and 17 kDa essential SM myosin light chain (MLC) pre-mRNAs. Our aim was to examine the relative SM myosin isoform composition in human CC. Tissue samples were obtained from 18 patients with erectile dysfunction (ED), Peyronie's disease, or both. One specimen was obtained during a transgender operation. Patients then were stratified according to presence of diabetes mellitus, hypertension, ED, or Peyronie's disease, as well as failure of phosphodiesterase-5 (PDE5) inhibitors and history of previous pelvic or penile surgeries, radiation, or both. Our results revealed that all human CC samples expressed only the SM-A isoform. There was a predominance of SM2 isoform mRNA relative to SM1 across all samples, with a mean of 63.8%, which correlated with protein analysis by gel electrophoresis. A statistically significant difference was found between patients who had undergone previous pelvic surgery, radiation, or both and those who did not. The ratio of LC(17b) to LC(17a) was approximately 1:1 for all patients, with a mean of 48.9% LC(17b). Statistical difference was seen in the relative ratio of LC(17b) to LC(17a) among the group who failed conservative therapy with PDE5 inhibitors compared with all others. In conclusion, we determined the SM myosin isoform composition of human CC and present for the first time differences in relative myosin isoform expression among patients with several risk factors contributing to their cause of ED. Our data reflect the fact that alternative splicing events in the MHC and 17 kDa MLC pre-mRNA may be a possible molecular mechanism involved in the altered contractility of the CCSM in patients with ED.

Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patients each were given 500, 1000, and 5000 microg, and two patients were given 7500 microg, of hMaxi-K and monitored for 24 weeks. The primary objectives of this phase I study were safety and tolerability of escalating hMaxi-K doses as assessed by clinical evaluations and laboratory tests. Secondary efficacy objectives were measured primarily by use of the International Index of Erectile Function (IIEF) scale. Patient responses were validated by partner responses. There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry, and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function (EF) as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study. Efficacy conclusions cannot be drawn from results of a phase I trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of ED and that further studies investigating the efficacy of hMaxi-K in patients with ED should be performed.

Objective: To investigate whether variable coding sequence protein A1 (Vcsa1) is down-regulated in rat models of diabetes and ageing, and to investigate the role of Vcsa1 in erectile function, as Vcsa1 is the most down-regulated gene in the corpora of a rat model of neurogenic erectile dysfunction (ED)., Materials and Methods: Quantitative reverse-transcriptase polymerase-chain reaction was used to determine Vcsa1 expression in the corpora of rats in three models of ED, i.e. streptozotocin-induced diabetes, retired breeder (old), and neurogenic (bilaterally ligated cavernosal nerves), and in control rats. To confirm a physiological role of Vcsa1 in erectile function, we carried out gene transfer studies using a plasmid in which Vcsa1 was expressed from a cytomegalovirus promoter (pVAX-Vcsa1). This plasmid was injected intracorporally into old rats, and the effect on physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement and histological analysis, and compared with the effects of a positive control plasmid (pVAX-hSlo, which we previously reported to restore erectile function in diabetic and ageing rats) and a negative control plasmid (pVAX)., Results: In each rat model of ED there was a significant down-regulation of the Vcsa1 transcript of at least 10-fold in corporal tissue. Remarkably, intracorporal injection with 80 microg pVAX-Vcsa1 caused priapism, as indicated by visible prolonged erection, histological appearance, and elevated resting ICP/BP. Lower doses of pVAX-Vcsa1 (5 and 25 microg) increased ICP/BP over that in untreated controls., Conclusion: These results show that Vcsa1 has a role in erectile function and might be a molecular marker for organic ED. The role of Vcsa1 in erectile function suggests that it could represent a novel therapeutic target for treating ED.

Objective: To establish the methods, feasibility and utility of evaluating the impact of diabetes on bladder and erectile function in the same rat, as more than half of diabetic patients have bladder dysfunction, and half of diabetic men have erectile dysfunction, but the severity of coincident disease has not been rigorously assessed., Materials and Methods: In all, 16 F-344 rats had diabetes induced by streptozotocin (STZ), and were divided into insulin-treated (five) and untreated (11), and compared with age-matched controls (10), all assessed in parallel. All STZ rats were diabetic for 8-11 weeks. Cystometric studies were conducted on all rats, with cavernosometric studies conducted on a subset of rats., Results: There were insulin-reversible increases in the following cystometric variables; bladder weight, bladder capacity, micturition volume, residual volume, micturition pressure and spontaneous activity (P < 0.05, in all, one-way analysis of variance, anova). Cavernosometry showed a diabetes-related, insulin-reversible decline in the cavernosal nerve-stimulated intracavernosal pressure (ICP) response at all levels of current stimulation (P < 0.05, in all one-way anova). Plotting erectile capacity (i.e. ICP) against bladder capacity showed no correlation between the extent of the decline in erectile capacity and the magnitude of the increase in bladder capacity., Conclusions: These studies extend previous work to indicate that the extent of diabetes-related bladder and erectile dysfunction can vary in the same rat. As such, these findings highlight the importance of evaluating the impact of diabetes on multiple organ systems in the lower urinary tract. Future studies using this model system should lead to a better understanding of the initiation, development, progression and coincidence of these common diabetic complications.

To determine whether the results of the self-reported International Index of Erectile Function (IIEF) to assess erectile function can overestimate the degree of erectile impairment. A total of 32 consecutive patients seeking treatment for erectile dysfunction (ED) at a urologist's office were evaluated by completion of the erectile function domain of the IIEF. Nocturnal penile tumescence testing using the Rigiscan (Timm Medical Technologies Inc., USA) was performed in these patients after completion of the IIEF. The median IIEF-6 score was 9 of 30 (range, 1-25; mean, 11/30). Rigiscan results were abnormal in six patients (19%), normal in 25 patients (78%), and unable to interpret in one patient (3%). IIEF-6 scores were subdivided by severity along with Rigiscan results. There was no correlation between age, IIEF score, or Rigiscan results. In conclusion, the IIEF is a useful tool and is helpful for follow-up of a patient to evaluate efficacy of treatments for ED, but should not replace objective testing to diagnose the quality of ED.

The promise of gene therapy to treat diseases remains largely unfulfilled. Past setbacks and the complexity of the delivery systems used, in terms of both targeting the appropriate cells and inducing expression of products at therapeutic levels, thus far have prevented significant success for gene therapy. Smooth muscle disorders represent a unique target for gene therapy. In many cases, smooth muscle is readily accessible and, to induce a therapeutic effect, will not require very high levels of gene product expression. This allows a lower efficiency of gene transfer to be successful. With these important features in mind, we believe that naked DNA transfer of potassium ion channels represents a novel and successful way to treat smooth muscle disorders. Herein, we present a rationale for treating erectile dysfunction, a smooth muscle disorder of the cavernosal bodies of the penis, with naked DNA gene transfer therapy. By inserting the hSlo gene, which codes for Maxipotassium channels, into smooth muscle cells, we can improve smooth muscle relaxation in the corporal bodies and thus improve erectile function. This method of gene transfer has proven to be safe and effective for erectile dysfunction, and human trials are ongoing.

Gene transfer represents the next potential era of advancement in medicine for the prevention of the effects of aging or for treatment of genetic or acquired disease. For gene transfer to be a practical successor to today's oral and minimally invasive therapies, the product must have a high safety profile and a long duration of effectiveness to correct the need for on-demand administration. Several types of vectors have been used in preclinicals studies, but because of widely publicized adverse events, progress using viral vectors in humans has been limited. There is a current phase I human trial using naked DNA as the vector with the maxi-K gene to modify cellular contractility. Preliminary results in the safety trial thus far have shown no treatment-related adverse events, no transfer to the semen, and the possibility of efficacy in one participant.

Objective: To test the safety of a single intracavernous injection of a plasmid vector (hMaxi-K) that expresses the hSlo gene, that encodes the alpha-subunit of the Maxi-K channel, for the treatment of erectile dysfunction (ED)., Methods: Six men, thus far have fulfilled the entry criteria of the protocol and had gene transfer with hMaxi-K. Three received a dose of 500 microg and three received a dose 1000 microg of the gene product, injected intracavernously as naked DNA. Dosing at 5000 microg and higher is planned., Results: The primary end point of the phase I trial is safety. No drug-related adverse events or significant laboratory changes have occurred after the gene transfer. Moreover, there is no evidence of the gene in semen at the one copy per mug total DNA in any of the participants., Conclusion: Preliminary results indicate that, in a single dose escalation study, ion channel gene transfer with hMaxi-K can be administered safely to men with ED without adverse events.

The ability of gene transfer with the pore-forming subunit of the human maxi-K channel (hSlo) to ameliorate the decline in erectile capacity commensurate with 12-24 wk of streptozotocin (STZ)-diabetes was examined in 181 Fischer-344 rats. A 2-mo period of STZ-diabetes was induced before gene transfer, and erectile capacity was evaluated by measuring the intracavernous pressure response (ICP) to cavernous nerve (CN) stimulation (ranging from 0.5 to 10 mA). In the first series of experiments, ANOVA revealed increased CN-stimulated ICP responses at 1 and 2 mo postinjection of 100 microg pcDNA-hSlo compared with control values. A second series of experiments further examined the dose dependence and duration of gene transfer. The ICP response to submaximal (0.5 mA) and maximal (10 mA) nerve stimulation was evaluated 3 or 4 mo postinjection of a single dose of pcDNA-hSlo ranging from 10 to 1,000 microg. ANOVA again revealed that hSlo overexpression was associated with increased CN-stimulated ICP responses compared with responses in corresponding control animals. Histological studies revealed no immune response to the presence of hSlo. PCR analysis documented that expression of both plasmid and transcript were largely confined to the corporal tissue. In the third series of pharmacological experiments, hSlo gene transfer in vivo was associated with iberiotoxin-sensitive relaxation responses to sodium nitroprusside in corporal tissue strips in vitro. The latter data indicate that gene transfer produces functional maxi-K channels that participate in the modulation of corporal smooth muscle cell tone. Taken together, these observations suggest a fundamental diabetes-related change in corporal myocyte maxi-K channel regulation, expression, or function that may be corrected by expression of recombinant hSlo.

Purpose: We have previously reported that 1 intracorporeal injection of 100 microg hSlo/pcDNA reversed the effect of aging on erectile function in a rat model in vivo for at least 2 months. We report our further investigations of the amplitude, duration and physiological relevance of this novel gene transfer approach., Materials and Methods: A total of 191 retired breeder Sprague-Dawley rats were given a single intracavernous injection of phosphate buffered saline, 1,000 microg pcDNA, or 10, 100 or 1,000 microg pcDNA/hSlo. The animals were studied 1 to 6 months after injection. The intracorporeal pressure (ICP) response to cavernous nerve stimulation and immunostaining as well as hematoxylin and eosin staining were done to evaluate effector nerve integrity and tissue histology, respectively., Results: Gene transfer prevented an age related decrease in resting ICP and a physiologically relevant, significant effect on normalizing erection in vivo, as determined by submaximal (0.5 mA) and maximal (4.0 mA) cavernous nerve stimulation. The effects were observed 1 month after transfection and sustained for 6 months at the 100 and 1,000 microg doses of pcDNA/hSlo (p <0.026)., Conclusions: The physiological manifestations of gene transfer were detected as an amelioration of the age related decrease in resting ICP, and parallel increase in the magnitude of the cavernous nerve stimulated an ICP response to a level at which visible erections were again observed in this rat model of aging in vivo.

Purpose: Quantitative somatosensory testing, including vibration, pressure, spatial perception and thermal thresholds of the penis, has demonstrated neuropathy in patients with a history of erectile dysfunction of all etiologies. We evaluated which measurement of neurological function of the penis was best at predicting erectile dysfunction and examined the impact of location on the penis for quantitative somatosensory testing measurements., Materials and Methods: A total of 107 patients were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire, of whom 24 had no complaints of erectile dysfunction and scored within the "normal" range on the IIEF. Patients were subsequently tested on ventral middle penile shaft, proximal dorsal midline penile shaft and glans penis (with foreskin retracted) for vibration, pressure, spatial perception, and warm and cold thermal thresholds., Results: Mixed models repeated measures analysis of variance controlling for age, diabetes and hypertension revealed that method of measurement (quantitative somatosensory testing) was predictive of IIEF score (F = 209, df = 4,1315, p <0.001), while site of measurement on the penis was not. To determine the best method of measurement, we used hierarchical regression, which revealed that warm temperature was the best predictor of erectile dysfunction with pseudo R(2) = 0.19, p <0.0007. There was no significant improvement in predicting erectile dysfunction when another test was added. Using 37C and greater as the warm thermal threshold yielded a sensitivity of 88.5%, specificity 70.0% and positive predictive value 85.5%., Conclusions: Quantitative somatosensory testing using warm thermal threshold measurements taken at the glans penis can be used alone to assess the neurological status of the penis. Warm thermal thresholds alone offer a quick, noninvasive accurate method of evaluating penile neuropathy in an office setting.

These studies were intended to explore the relationship between autonomic neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the integrity of both large diameter, myelinated neurons (ie pressure, touch, vibration) and small diameter axons (ie hot and cold thermal sensation) were determined on the penis and finger. Data were compared across subjects with and without ED, controlling for age, hypertension and diabetes. The correlation of specific thresholds scores and IIEF values were also examined. Seventy-three patients who visited the academic urology clinics at Montefiore hospital were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire: 20 subjects had no complaints of ED and scored within the 'normal' range on the IIEF. Patients were subsequently tested on their index finger and glans penis for vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial perception (Tactile Circumferential Discriminator), and warm and cold thermal thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the examined sensory thresholds, was significantly diminished in patients with ED and these differences remained significant when controlling for age, diabetes and hypertension. In contrast, thresholds on the index finger were equivalent in the ED and non-ED groups. Threshold and IIEF scores were highly correlated, consistent with an association between diminished sensation and decreasing IIEF score (worse erectile functioning). These relations also remained significant when controlling for age, diabetes and hypertension. The findings demonstrate dysfunction of large and small diameter nerve fibers in patients with ED of all etiologies. Further, the neurophysiologic measures validate the use of the IIEF as an index of ED, as objective findings of sensory neuropathy were highly correlated with worse IIEF scores. The sensory threshold methods utilized represent novel, non-invasive and relatively simple procedures, which can be used in a longitudinal fashion to assess a patient's neurological response to therapies.

The past few years have been witness to a sea of change in understanding the diagnosis and treatment of erectile dysfunction. In the wake of Viagra, effective orally administered therapies are now the expected gold standard. Currently available therapies include both peripherally (at the level of the penis) and centrally (brain, e.g., hypothalamic nuclei) acting compounds. When all modes of pharmacotherapy are considered, ranging from oral, to topical, to intraurethral, to intracavernous injection, it is clear that the vast majority of men with mild to moderate erectile dysfunction can now be effectively treated. However, all forms of pharmacotherapy have the lowest efficacy and greatest side effect profiles (including cardiovascular events) in the patients that need the therapy most, that is, those with relatively severe and longstanding erectile dysfunction. The newer generation of pharmacotherapies, which will likely include gene therapy techniques as well, will therefore have to target this latter group. Improved mechanism-based, perhaps patient-specific therapies are foreseen that will dramatically increase the number of patients seeking treatment, as well as the quality of their lives.

Purpose: Sustained contraction of human corporeal smooth muscle depends on continuous transmembrane calcium flux through voltage gated calcium channels. K channels modulate corporeal smooth muscle membrane potential and, thus, ultimately affect transmembrane calcium flux. Therefore, we characterized relaxation responses elicited by the K channel modulators pinacidil and levcromakalim on isolated human corporeal tissue strips. We also evaluated the possibility that there may be alterations in adenosine triphosphate sensitive K channel pharmacology/function related to the presence of diabetes mellitus., Materials and Methods: A total of 215 isolated human corporeal tissue strips obtained from 57 male patients with organic erectile dysfunction were investigated. Cumulative concentration-response curves were constructed at half log increments for steady state relaxation responses elicited by pinacidil and levcromakalim on equivalently phenylephrine pre-contracted (to approximately 75% of maximum) isolated corporeal tissue strips. Potassium currents were measured using the cell attached whole cell patch clamp technique on freshly isolated corporeal smooth muscle cells., Results: A concentration dependent, glibenclamide sensitive relaxation response of phenylephrine pre-contracted corporeal tissue strips was observed for pinacidil and levcromakalim. Consistent with such observations, electrophysiological recordings on freshly isolated myocytes revealed that pinacidil (10 microM.) and levcromakalim (10 microM.) induced whole cell potassium currents that were blocked by glibenclamide (10 microM.). In addition, statistical analysis revealed that phenylephrine pre-contracted corporeal tissue strips from patients without diabetes were more sensitive to relaxation by both compounds than corporeal tissue strips excised from those with diabetes. Furthermore, relaxation responses elicited by pinacidil and levcromakalim were not affected by charybdotoxin or 4-aminopyridine but were completely reversed by KCl or tetraethylammonium chloride., Conclusions: These data indicate that the adenosine triphosphate sensitive K channel subtype is likely to have an important role in the relaxation of isolated corporeal tissue strips and, moreover, they are the molecular target for the K channel modulators/openers levcromakalim and pinacidil. Such observations are consistent with the supposition that alterations in the structure/function/activity of these potassium channels may underlie at least some aspects of observed diabetes related differences in tissue sensitivity to K channel modulators.

Advances in molecular biological techniques, completion of the Human Genome Project, and the ensuing age of molecular medicine, in conjuction with the sum of a decades-long accumulation of knowledge of the physiology of erection and the pathophysiology of erectile dysfunction have converged to make gene therapy for erectile dysfunction a distinct possibility. In short, both the intrinsic complexities of mechanisms responsible for ensuring normal erection and the multifactorial nature of erectile dysfunction ensure that there is a relatively vast number of physiologically relevant molecular targets for gene therapy. As such, perhaps it is not surprising that virtually every preclinical gene therapy strategy/target examined thus far has been largely successful in ameliorating conditions associated with compromised erectile function in vivo and/or in vitro. This report highlights the goals and strategies of gene therapy for erectile dysfunction and reviews the strategies that initially have been employed. In short, the preclinical data, while still quite preliminary in many regards, are nonetheless quite impressive and encouraging. If similar success is obtained in clinical trials, gene therapy for erectile dysfunction may provide the first concrete "proof of concept" for using gene therapy in the treatment of human smooth muscle disorders.

Initiation, maintenance, and modulation of corporal smooth muscle tone are critically dependent upon agonist-induced changes in intracellular calcium levels and mobilization as well as transmembrane calcium flux. The transient control of myocyte excitability and contractility at the cellular level is inextricably linked to membrane potential, which, in turn, is modulated by potassium ion efflux through one of the four known corporeal smooth muscle potassium ion channels. Corporal tissue responses are subsequently coordinated by means of the movement of intracellular second messenger molecules (i.e., IP3, cAMP, cGMP) and ions (i.e., K+ and Ca2+) among the corporal myocytes by means of intercellular communication through gap junction channels. Knowledge of the critical contribution of these interlinking cellular (nonjunctional ion channels [e.g., maxi-K]) and tissue (gap junction channels [e.g., connexin 43]) systems to the modulation of erectile capacity has provided the scientific rationale for the promulgation of the successful preclinical testing of hSlo ion channel gene therapy for the normalization of erectile status in both aged and diabetic rats.

Purpose: Published studies on the epidemiology of erectile dysfunction and the physiology/ pathophysiology of erectile function are reviewed., Materials and Methods: A literature search of more than 400 studies of the epidemiology and pathophysiology of impotence and erectile dysfunction published during the last 3 decades was conducted and the most pertinent articles are discussed., Results: It has been estimated that the prevalence of erectile dysfunction of all degrees is 52% in men 40 to 70 years old, with higher rates in those older than 70 years. Erectile dysfunction has a significant negative impact on quality of life. Risk factors for erectile dysfunction include aging, chronic illnesses, various medications and cigarette smoking. A nitric oxide/cyclic guanosine monophosphate mechanism has an important role in mediating the corporal smooth muscle relaxation necessary for erectile function. Other mechanisms involving neuropeptides, gap junctions and ion channels also may modulate corporal smooth muscle tone. Erectile dysfunction can be due to vasculogenic, neurogenic, hormonal and/or psychogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mechanisms, resulting in an imbalance in corporal smooth muscle contraction and relaxation., Conclusions: Erectile dysfunction is a common condition associated with aging, chronic illnesses and various modifiable risk factors. Normal penile erection is a hemodynamic process that is dependent on corporal smooth muscle relaxation mediated by parasympathetic neurotransmission, nitric oxide, and possibly other regulatory factors and electrophysiological events. As more knowledge is gained of the physiology and regulatory factors that mediate normal erectile function, the mechanisms involved in the pathophysiology of erectile dysfunction should be further elucidated.

Purpose: The computer generated recordings for 2 nights in 40 patients studied with the RigiScan device were reevaluated using the new RigiScan Plus software to test its value in improving the discrimination between psychogenic and organic erectile dysfunction., Materials and Methods: Each man was evaluated for erectile dysfunction with a detailed medical and sexual history, physical examination, biothesiometry, plethysmography, 2 nights of ambulatory RigiScan monitoring and a psychological evaluation that usually included a private interview with the sexual partner. At the conclusion of evaluation each patient was broadly classified as having organic or psychogenic erectile dysfunction. The RigiScan reports were initially independently analyzed without the investigator's knowledge of the final diagnosis by determining the single best erectile event, with a minimal cutoff value of 60% erection for 5 minutes as necessary to be considered normal and the sum of measurements from the 2 nights. The original reading and final diagnosis were correlated. At this point the data were processed with the new RigiScan Plus software using 2 new measurements: 1) rigidity activity units and 2) tumescence activity units at the base and tip of the penis, and the results were correlated with the final diagnosis., Results: Evaluation of the single best event again showed that tip rigidity was the best single predictor if the diagnostic criteria were modified to 70% tip rigidity for 5 minutes with an estimate of correct classification of 92.5%. Nearly the same accuracy was obtained by base single event rigidity, tip rigidity and base tumescence activity units (each 90%). The summary analysis of all erectile events during the 2 nights of evaluation that had a low correlation with the final diagnosis using the original software showed that the best overall predictor of final diagnosis was tip tumescence activity units (92.5%), followed by base rigidity and tumescence activity units (each 90%)., Conclusions: The RigiScan Plus software introduced 4 new parameters that facilitate interpretation of the RigiScan data. The new software did not improve the correlation with the final diagnosis compared to the subjective single best event analysis but added new objective parameters, measured and displayed by the software, that facilitate use of the data by the physician.

Fifty per cent of men with diabetes have erectile dysfunction. Previous studies demonstrated that cultured smooth muscle cells from corpus cavernosum display significantly altered K+ channel function, PGE-induced cAMP accumulation, and endothelin-1 induced Ca2+ mobilization that are consistent with the pathophysiology of erectile dysfunction. Since defects in signal transduction frequently lead to altered gene expression, we examined differences in gene expression in corporal tissue excised from three diabetic patients with erectile dysfunction function and one patient with neurogenic erectile dysfunction. Using differential display, we identify a transcript expressed in tissue derived from the patient with impotence secondary to a radical prostectomy, but which was greatly reduced or absent in corporal tissue from all three diabetic patients examined. DNA sequence analysis indicates that this transcript has no significant homology to sequences presently deposited in the GenBank database. This suggests that altered gene expression may play a significant part in the etiology of erectile dysfunction.

The importance of the nitric oxide--guanylate cyclase--cGMP system in modulating corporal smooth muscle tone and penile erection has been amply demonstrated. The goal of these studies was to evaluate the possibility that age- or disease-related alterations in human corporal smooth muscle responsivity to activation of this pathway might play a role in the etiology of erectile dysfunction. Thus, we utilized a previously described heuristic model to assess the kinetic and steady-state characteristics of relaxation of precontracted isolated corporal tissue strips elicited by nitroglycerine (NTG). Studies were conducted on corporal tissue strips excised from 26 patients with organic erectile dysfunction, and 7 patients with documented erections. For the purposes of statistical analysis the impotent patient population was stratified into two age groups (A, < or = 59 years; B, > or = 60 years) and further subdivided into two diagnostic categories, diabetic and nondiabetic patients, respectively. In approximately 75% of precontracted corporal tissue strips derived from impotent patients (contracted to approximately 75% of maximum with phenylephrine), the NTG-induced response was biphasic, consisting of a rapid relaxation response that reached steady state before onset of a more slowly developing regaining of tension, termed the desensitization response. In contrast, a biphasic response was observed much less frequently (approximately 30%) in corporal tissue strips derived from a potent patient population (p < 0.0001). Statistical analysis revealed significant heterogeneity among corporal tissue strips derived from patients with organic erectile dysfunction, with respect to both the kinetic and steady-state characteristics of the NTG-induced relaxation and desensitization responses. In particular, the maximal rate constant for both NTG-induced relaxation (krelmax; p < 0.01) and desensitization (kdes; p < 0.03) responses was significantly greater in corporal tissue strips excised from diabetic than nondiabetic patients. Furthermore, the EC50 for NTG-induced relaxation of precontracted corporal smooth muscle strips from potent patients (approximately 25 nM) was 0.90 log unit less than that for equivalently contracted corporal smooth muscle strips derived from impotent patients (approximately 180 nM; p < 0.03). Such observations suggest that alterations in corporal smooth muscle responsivity to activation of the guanylate cyclase--cGMP pathway, per se, may be a characteristic of organic erectile dysfunction. In the absence of compensatory changes in other vasodilatory mechanisms, this may contribute to incomplete corporal smooth muscle relaxation and the etiology of erectile dysfunction in some patients.

Of 20 men evaluated for erectile dysfunction (ED) for whom vacuum erection devices or constriction bands were recommended, only four experienced improvement of their erectile function by using the specific suggested method. Although use of a simple constriction band mechanism (e.g., a rubber band wound tightly around the penis) for men with brief erectile capacity has been described as a viable treatment, only one of five men who tried using it achieved any success. Three of six men who used a vacuum erection device were helped by it, particularly the men who suffered from only partial ED. Most patients did not follow through with the recommended treatment and stopped sexual activity, or belatedly returned for intracavernosal injections. The interviews revealed the pervasive influence of shame and demoralization regarding erectile problems, the importance of evaluation and treatment follow-up, and the necessity for careful, explicit, extensive, and concrete explanations and instructions regarding treatment options.

During the last two decades, significant advances have been made in the understanding of male sexual dysfunction. Concomitantly, a marked increase in both clinical and research activity in the field of male erectile dysfunction has led to a better evaluation and more treatment options. The prevalence and incidence are dependent on the definitions used, the diagnostic tolls, and the treatment options. Using standard definitions as suggested by the NIH Consensus Conference and improving our diagnostic and treatment options will have a major impact on the epidemiology of ED. A summary of the risk factors for ED is presented in Table 3. Still more epidemiologic research is essential to further understand the distribution as well as the prevalence of ED in certain ethnic groups, chronic conditions, and as a result of surgery and trauma. These studies will help us improve our diagnostic skills as well as our therapeutic options.

Normal erectile physiology is heavily dependent on a delicate balance between the effects of endogenous vasoconstricting and vasorelaxing hormones on the tone of the corporal smooth muscle. Recent studies indicate that endothelin-1 (ET-1) is present and physiologically active in the human corpora. The primary goal of the present investigation was to further define the role of ET-1 in corporal physiology and to ascertain whether it might play a role in augmenting corporal tone in vivo, as reported in other vascular tissues. Thus, we conducted pharmacological studies of ET-1-induced steady-state contractions in isolated human corporal smooth muscle strips to determine if there were any detectable age- or diabetes-related alterations in ET-1-induced contractions. For statistical analysis, the patient population was divided into 2 age groups, A (< or = 59 years of age; = 11 patients) and B (> or = 60 years of age; n = 7 patients), and further subdivided into 2 diagnostic categories, diabetic (n = 7 patients) and nondiabetic (n = 11 patients). Construction of cumulative concentration response curves (CRCs) for ET-1-induced contractions revealed characteristically slow onset and long-lasting responses. Endothelin-1 CRC data were computer fit to the logistic equation to derive Emax (calculated maximal response), pEC50 (negative logarithm of the concentration that elicits one-half of the calculated maximal response) and slope factor (n) values. Two-factor analysis of variance revealed no detectable age- or diabetes-related alterations, nor any age-diabetes interaction in any of the logistic parameters. Furthermore, logistic analysis of ET-1 CRC data on 14 isolated corporal tissue strips derived from 3 potent patients with documented spontaneous erections revealed no differences in ET-1 contractility from that observed for patients with organic erectile dysfunction. Importantly, despite an apparent absence of age- or diabetes-related alterations in ET-1-induced steady-state contractions, preliminary studies demonstrated that coadministration of the alpha 1-adrenergic agonist phenylephrine and ET-1 produce much greater contractile responses than those observed in the presence of phenylephrine (PE) alone. Moreover, the magnitude of the augmentation was precisely that predicted by a model for simple additivity of agonist effects. Such observations suggest that the physiological relevance of ET-1 to corporal physiology may be related to its ability to augment the contractile responses of other vasomodulators present in the human corpora, in particular, perhaps modulating the contractile responses to sympathetic activity.

Objectives: Because of its implications for possible therapy, the ability to establish a diagnosis of erectile dysfunction (ED) solely on the basis of history and physical examination has been a matter of controversy. The determination of the etiology of ED based on history and physical examination is evaluated in this present study., Methods: Consecutive patients presenting for evaluation of ED were evaluated by careful history, physical examination, psychologic evaluation, and RigiScan monitoring. They were then stratified into either organic or psychogenic groups based on each of these modalities. These diagnoses were then compared to a final diagnosis obtained through additional testing., Results: History and physical examination had a 95% sensitivity but only a 50% specificity in diagnosing organic ED. The accuracy rates of history and physical examination in diagnosing ED were 80% and 60%, respectively., Conclusions: A multifaceted comprehensive approach is required to evaluate fully and to diagnose ED.

We report our long-term results of a self-injection program, in a large number of patients, at our sexual dysfunction center. The results demonstrate the efficacy of the polydrug solution of papaverine-phentolamine-prostaglandin E1 in terms of a long-term durable response with a reduction in side-effects.

Until the early 1970s impotence was believed to be primarily a psychological disorder. The treatment usually consisted of empiric testosterone administration and psychotherapy, that were often ineffective. The introduction in the early 1970s of penile implants changed the treatment options and at the same time ushered in the modern era of male sexual medicine. Clinical as well as laboratory research improved significantly the diagnosis and treatment options of the impotent man. Today the man with a sexual problem has a much better chance of proper diagnosis and effective treatment.

We studied the pathological specimens obtained from 24 impotent men who underwent proximal penile vein ligation and 6 potent men who underwent total penectomy as part of male-to-female transsexual surgery to determine if a correlation exists between venous pathology and surgical outcome. Pathology specimens, consisting of cavernosal tissue and penile veins, were independently reviewed by a single uropathologist (V. A.). The degree of vein wall thickness was carefully quantified for each patient. Venous leakage was documented by cavernosometry and cavernosography. Followup ranged from 7 to 19 months (mean 11 months). Within 6 months of the procedure 10 patients (41%) achieved rigid erections while 14 (59%) did not. Although no preoperative index could predict operative success, in the 10 patients with successful outcome histological examination of the excised vein segments revealed normal venous architecture with minimal vein wall thickness (calculated mean per cent vein wall thickness 39.4, range 17.5 to 51.7). In contrast, in the 14 patients in whom ligation failed there was marked vein wall thickness and sclerosis (calculated mean per cent vein wall thickness 68.0, range 55.3 to 85.6). In comparison, the vein segments obtained from the 6 potent patients had a wall thickness of 32.8% (range 8 to 39), which was equivalent to the 10 patients with postoperative erections. These findings suggest that there may be a correlation between vein wall thickness and the prognosis of patients who undergo venous ligation surgery for erectile dysfunction secondary to presumed corporeal venous incompetence.

Coronary bypass surgery to provide better blood flow to deficient areas of the heart is commonplace; the arteries of the heart in which blockage occurs are relatively large, and rerouting of blood is readily accomplished. In the penis, the internal pudendal system that provides arterial inflow can be easily bypassed when injury to a large vessel is the cause of erectile dysfunction. In the great majority of cases of penile arterial disruption, however, large-vessel disease cannot be demonstrated; the problem of low arterial flow originates within the corpora cavernosa, in the so-called helicine arteries. These arteries are very small, and are inaccessible unless the spongy erectile tissue of the corpora cavernosa is violated. In recent years, modest success has been reported in revascularizing the smaller arteries of the penis. The expert panelists in this symposium discuss the indications for such revascularization procedures, compare their techniques, and review the success rate in their work.

The treatment of arteriogenic erectile dysfunction with revascularization techniques has been controversial both in terms of its use and the type of surgical repair. Success rates reported in the literature are based almost exclusively on patient testimonial, without the use of objective post-operative criteria. At our institution from 7/88 through 8/91, 18 patients were treated for arteriogenic impotence using microsurgical penile revascularization. The patient population ranged in age from 23 to 64 years, and each patient underwent a complete history and physical examination, serum hormone testing, psychological evaluation of patient and partner, biothesiometry, penile plethysmography, nocturnal penile tumescence/rigidity testing with a Rigiscan device, and selective pudendal arteriography. One patient was status post a pelvic fracture, 2 lacked identifiable risk factors, 2 had diabetes, 6 were heavy smokers, and 7 had hypertension. Pre-operatively each patient had a suspicious medical history, abnormal plethysmography, abnormal Rigiscan testing, and a hemodynamically significant lesion on angiography. Revascularization was done by anastomosing the inferior epigastric artery to the deep dorsal veing and dorsal artery, or the deep dorsal vein alone if both arteries were atretic. Postoperatively, all 18 patients underwent a personal interview, repeat penile plethysmography, and repeat Rigiscan testing. Six patients reports successful coitus and an additional four were having coitus with the aid of intracavernous pharmacotherapy. Seventy-eight percent (14/18) had improved tracings on penile plethysmography, and 56% (10/18) had normal erectile capability by Rigiscan testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have noted the abundance of collagen in human erectile tissues and the association of altered collagen content with erectile dysfunction. We investigated these notions by studying the collagen characteristics of biopsies from the corpus cavernosum of men who required surgical correction of their sexual dysfunction. Histologic analysis revealed abundant collagen within the erectile tissues. With the exception of patients with Peyronie's disease and priapism, only mild alterations in collagen architecture were noted in the remainder of the patients. Biochemical quantitation confirmed the histologic study. The mean collagen content represented 47% of total protein in most patients. The proportion rose to 68% and 73% in the patients with Peyronie's disease and priapism, respectively. No statistical difference in collagen content was noted in all the patients studied. Immunohistochemistry revealed collagen types I and IV to predominate in the corpus cavernosum, with type III making up the minority. There were no qualitative changes in collagen ratios with age and disease. We conclude that though collagen is a major component of the penis, there are no changes in its histologic characteristics that can be correlated to senescence or to the etiology of erectile dysfunction.