Pelvic organ prolapse is associated with alteration of sphingosine-1-phosphate/Rho-kinase signalling pathway in human vaginal wall.

Pelvic organ prolapse (POP) is a debilitating condition of unknown aetiology affecting > 50% of women over 40 years of age. In POP patients, the vaginal walls are weakened allowing descent of pelvic organs through the vagina. We sought to determine if sphingosine-1-phosphate (S1P) signalling, which regulates smooth muscle contractility and apoptosis via the RhoA/Rho-kinase (ROK) pathway, is altered in the vagina of women with POP. Utilising anterior vaginal wall specimens, we provide novel demonstration of the S1P pathway in this organ. Additionally, comparing specimens from women having pelvic reconstructive surgery for POP and control subjects, we reveal increases in mRNA expression of the three major mammalian S1P receptors (S1P1-S1P3), and RhoA and the ROK isoforms: ROKα and ROKß in POP patients, which correlates with a decrease in elastic fibre assembly pathway constituents. Taken together, our data suggest the S1P/ROK pathway as a novel area for future POP research and potential therapeutic development.

Effect of once-daily tadalafil on confidence and perceived difficulty in performing sexual intercourse in men who were incomplete responders to as-needed PDE5 inhibitor treatment.

INTRODUCTION: For men with erectile dysfunction (ED), the expectation of difficulty and level of confidence in achieving and maintaining an erection have an impact on sexual performance. OBJECTIVE AND METHODS: This 12-week, double-blind study investigated once-daily tadalafil (2.5 mg titrated to 5 mg or 5 mg) (n = 176) or placebo (n = 79) on confidence and perceived difficulty in performing sexual intercourse in men with ED who were incomplete responders to as-needed phosphodiesterase-5 inhibitor therapy. The Confidence in Performing Sexual Intercourse Questionnaire (CPSIQ) and Difficulty in Performing Sexual Intercourse Questionnaire (DPSIQ) were administered at baseline and 12 weeks. RESULTS: The mean change in CPSIQ for the tadalafil group was 1.8, which represents a shift from 'very low' to 'moderate' sexual confidence vs. a mean change of 0.5 in the placebo group (p < 0.0001). The mean change in DPSIQ for tadalafil was 1.6, which represents a shift from 'very difficult' to 'moderately' or 'slightly difficult' sexual performance vs. a mean change of 0.4 in the placebo group (p < 0.0001). Among men receiving tadalafil with an International Index of Erectile Function-Erectile Function (IIEF-EF) end-point score of ≥ 26 or who achieved a minimal clinically important difference in IIEF-EF score at end-point, the mean changes in CPSIQ were 3.0 and 2.4, respectively (both p < 0.0001). CONCLUSION: Once-daily tadalafil vs. placebo improves confidence and decreases difficulty in performing sexual intercourse for men with ED who were incomplete responders to as-needed PDE5 inhibitor therapy.

The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.

Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data.

OBJECTIVE: Assess and categorise the available prevalence data on coexistent LUTS and ED in the general population and among individuals consulting a healthcare provider for any reason or when seeking treatment for LUTS and/or ED. METHODS: Literature search of English-language articles published during the last 15 years. RESULTS: Of 23 relevant studies identified, 12 used both the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) as assessment tools and 11 used alternative approaches. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS/ED of any severity was not assessable for men in the general population, but rates ranged from 14-37% based on alternative assessments. In the general male population, 13-29% had moderate to severe LUTS and 8-35% had moderate to severe ED. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS and ED of any severity was 71-80% among men seeking treatment for LUTS, and 74% based on alternative assessments. Among men who sought treatment for either condition, 67-100% had moderate to severe LUTS and 43-59% had moderate to severe ED. Coexistence of LUTS and ED increased with age, ranging from 59-86% among men aged 40s to 60s in primary care to 79-100% in treatment-seeking men with LUTS aged 50s to 70s. Impact on QoL varied, but health-related QoL was generally worse in treatment-seeking men compared with men in the general population. CONCLUSIONS: Although less than one-third of middle-aged and older men in the general population have coexisting LUTS and ED, most men seeking treatment for either LUTS or ED have both conditions. Symptom severity and impact on QoL in each condition increase when LUTS and ED coexist.

Retrospective analysis of the efficacy and safety of once-daily tadalafil in patient subgroups: men with mild vs moderate ED and aged <50 vs 50 years.

The aim of this post-hoc pooled-data analysis was to evaluate the effects of once-daily tadalafil in men with mild or moderate ED and aged <50 or 50 years. Data from three randomized controlled trials were analyzed. Analysis of covariance models included a term for ED severity and age group. The three coprimary outcome measures in the base studies were changes from baseline to end point in the mean International Index of Erectile Function Erectile Function (IIEF-EF) domain score and the mean per-patient percentage successful vaginal penetration and intercourse attempts. Irrespective of baseline severity, once-daily tadalafil 5 mg for 12 weeks compared with placebo significantly increased the mean: (1) IIEF-EF by 6.8; (2) percent successful penetration attempts from 70.1 to 91.3%; and (3) percent successful intercourse attempts from 33.4 to 76.8% (each P<0.001). Treatment-by-age-group interaction P-values for all three coprimary efficacy end points exceeded 0.10, indicating that tadalafil treatment effects did not differ by age <50 vs 50 years. Tadalafil was generally well tolerated.

Erectile dysfunction and testosterone screening with prostate specific antigen screening at age 40: are these three gender specific determinants additive for overall men's heath and do they improve traditional non-gender specific determinants to lessen cardiovascular risk and all-cause mortality?

AIMS: Assess support for a recommendation to add screening for both erectile dysfunction (ED) and hypogonadism to the initial medical evaluation of young-to-middle aged (≥ 40 years of age) men in light of recent guidelines suggesting prostate-specific antigen screening occur at that age. METHODS: A search of literature published from 1998 to 2009 was performed. Search terms included: ED combined with coronary artery disease (CAD), metabolic syndrome and hypogonadism, hypogonadism and ED, hypogonadism, ED and mortality. Articles were evaluated according to the Center of Evidence-Based Medicine. RESULTS: Both retrospective and prospective evaluations have demonstrated a strong relationship between ED, established cardiovascular risk factors, CAD and the potential occurrence of cardiovascular events. Low testosterone levels are associated with ED. Low serum total testosterone is an independent risk factor for both metabolic syndrome and type 2 diabetes and all-cause mortality. CONCLUSION: Traditionally, ED and testosterone levels have been considered mainly, if not exclusively, in the context of sexual health. The results briefly summarised herein and other recent reviews suggest that ED and hypogonadism are signals of future all-cause mortality and overall health status and thus move these evaluations into the broader arena of public health. Screening for ED and hypogonadism provide 'gender-specific determinants' to assess general metabolic and cardiovascular health risks in men. It is the opinion of the authors that this screening be performed in addition to the well-established non-gender-specific screening tests of lipids, blood pressure, obesity and serum glucose.

Hypogonadism in men with erectile dysfunction may be related to a host of chronic illnesses.

The prevalence of hypogonadism has been found to be increased in certain chronic illnesses, especially diabetes, hypertension and obesity. Recently, the prevalence of hypogonadism in primary care practices mirrored that in our population of men with erectile dysfunction (ED). In this study, the prevalence of hypogonadism in nearly 1000 men with ED was tabulated, using a retrospective chart review, and analyzed for association with the various contributing medical and psychological factors. The prevalence of hypogonadism was determined in men with a variety of chronic illnesses, and was further characterized by decade. We observed an association between hypertension (P=0.025), tobacco abuse (P=0.0059), sleep apnea (P=0.0001), work stress (P=0.041) and hypogonadism. These data were further analyzed for the odds ratio and confidence interval (Forest plot), which showed strong association for sleep apnea and work stress. We did not observe any significant association between diabetes, atherosclerosis, alcohol abuse, multiple medications, asthma, seizure disorder, anxiety/depression and hypogonadism (P values for Cochran-Mantel-Haenszel general association were 0.48, 0.97, 0.25, 0.69, 0.22, 0.76 and 0.98, respectively). We suggest that a host of chronic illnesses have a high prevalence of secondary hypogonadism. Men who have chronic medical or psychological illnesses should have their testosterone level checked, especially when sexual dysfunction symptoms or signs are present.

Improvements in confidence, sexual relationship and satisfaction measures: results of a randomized trial of tadalafil 5 mg taken once daily.

An efficacy study of tadalafil (5 mg once daily) for treating erectile dysfunction included sexual satisfaction and psychosocial outcome measures such as Treatment satisfaction (THX) domain of Sexual Life Quality Questionnaire, Self-Esteem And Relationship (SEAR) questionnaire, Sexual Encounter Profile questions 4 (SEP4; hardness satisfaction) and 5 (SEP5; overall satisfaction), intercourse satisfaction (IS) and overall satisfaction (OS) domains of International Index of Erectile Function (IIEF), and partner SEP question 3 (pSEP3). After a 4-week run-in phase, participants were randomized to receive either tadalafil (N=264) or placebo (N=78) for 12 weeks. Participants and partners were more satisfied (THX) with tadalafil (75 and 73, respectively) than with placebo (51 and 55, respectively, P<0.001). Statistically significant improvements in sexual relationship, confidence, self-esteem and overall relationship (SEAR), in addition to IS, OS, SEP5 and pSEP3 for tadalafil compared with placebo (P<0.001) correlated with erectile function (EF) improvement (assessed by change from baseline in IIEF-EF score). Tadalafil significantly improved treatment and sexual satisfaction, while improving multiple outcomes measured by SEAR.

Impact of an educational initiative on applied knowledge and attitudes of physicians who treat sexual dysfunction.

A randomized, blinded, multicenter, controlled study was undertaken to assess the impact of a multiyear continuing medical education (CME) initiative on physician knowledge and behavior in the treatment of erectile dysfunction (ED). The objective of this study was to assess the efficacy of CME and compare applied knowledge and attitude scores of participants in the Consortium for Improvement in Erectile Function (CIEF), to non-CIEF participants. Subjects were selected randomly and contacted anonymously, by mail, email and fax and requested to enroll in this study. A blinded, validated questionnaire and series of standardized patient (SP) case studies and attitude questions were given to CIEF participants, defined as those who showed an interest in learning more about ED and who took at least one CME-certified program on ED from the CIEF website and non-CIEF participants, defined as those who showed interest in learning more about ED and who took at least one CME-certified program on ED from any organization other than CIEF. The primary outcome was a comparison of subjects' scores who participated in at least one CIEF program to non-participants in CIEF programs. Subjects were also compared based on SP case scores, attitude scores, specialty, years in practice, age and gender. Answers were ranked from best to worst and assigned a corresponding value of 10...3, 2, 1 and 0 (10 being the best), assuming that there may be more than one correct answer to each question in clinical practice. SAS version 9.1 analysis of variance model was used by an independent consultant. A total of 120 physicians completed the questionnaire: 87 urologists (UROs) and 33 primary care physicians (PCPs). UROs scored higher on SP cases compared with PCPs (P=0.0039); however, as a result of participating in CIEF programs, PCPs trended toward more comparable scores to UROs; P=0.23 for SP case 2 that was clinically less complex and P=0.19 for SP case 3 that was more complex. In the other two cases, the gap was reduced; however, UROs scored better than PCPs. PCPs in CIEF (n=23) had significantly higher SP case scores compared with non-CIEF PCPs (n=10); 216.6 vs 191.0, respectively (P=0.0437). PCPs in CIEF also showed a significantly greater level in mean attitude scores compared with UROs, 10.82 vs 8.15, respectively (P<0.0001). Both PCPs and UROs scored higher after participating in CIEF ED educational programs than those clinicians who participated in non-CIEF ED educational programs. In addition, clinicians participating in more CIEF programs scored higher than those participating in fewer CIEF programs. As expected, UROs consistently scored better than PCPs, indicating a higher baseline level of knowledge base about ED. However, this educational gap was significantly reduced in PCPs who participated in CIEF programs. The study demonstrated that PCPs who took more CIEF courses were almost as knowledgeable as UROs on the subject of ED. Longitudinal, disease-specific CME initiatives are valuable in that they positively impact the knowledge and thus the behavior of participating physicians, potentially conferring clinical benefits toward patient outcomes.

Validated questionnaires for assessing sexual dysfunction and BPH/LUTS: solidifying the common pathophysiologic link.

Erectile dysfunction (ED) and benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) share many epidemiologic and clinical similarities. First-line therapy for both conditions include oral medications (alpha blockers, phosphodiesterase inhibitors). The impetus to develop and use questionnaires to characterize these two conditions is based on the trend away from invasive diagnostic testing to the use of patient-reported outcomes or validated self-administered questionnaires. The International Prostate Symptom Score, the International Index of Erectile Function, the Male Sexual Health Questionnaire (MSHQ) and the MSHQ short form are similar patient-reported assessment questionnaires used for research or clinical evaluation of BPH/LUTS, ED and ejaculatory dysfunction. These patient-based self-administered questionnaires are likely to assume an ever increasing important role in the future, as oral BPH therapies are considered for the treatment of ED and oral ED therapies are considered for the treatment of BPH/LUTS.

Benign prostatic hyperplasia evaluation, treatment and association with sexual dysfunction: practice patterns according to physician specialty.

AIMS: Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) are a common problem in ageing men and are accompanied by sexual dysfunction (SD) in 40-70% of men evaluated in large-scale epidemiological studies. One year after the 2003 American Urological Association (AUA) guideline on BPH management was published, a survey of US urologists (UROs) and primary care physicians (PCPs) was conducted to ascertain physician knowledge of the AUA guideline and practice patterns regarding LUTS/BPH diagnosis, treatment and association with SD. METHODS: A 19-question qualitative survey, sponsored by the American Foundation of Urologic Disease, was mailed April 2004 to 7500 UROs and 17,500 PCPs, with responses collected until May 2004. RESULTS: A total of 788 surveys were returned (437 UROs; 351 PCPs). Only 62% of PCPs were aware of and only 41% of PCPs used the AUA-Symptom Index/International Prostate Symptom Score (AUA-SI/IPSS) to assess LUTS compared with 97% and 81% of UROs respectively. Alpha-blocker monotherapy was the treatment of choice for both UROs and PCPs. Compared with UROs, PCPs reported higher rates of SD in association with LUTS or BPH (37% vs. 27%) and BPH pharmacotherapy (27% vs. 21%). UROs and PCPs reported higher rates of SD side effects [ejaculatory dysfunction (EjD) and erectile dysfunction (ED)] for tamsulosin (EjD: UROs 22%, PCPs 12%; ED: UROs 7%, PCPs 10%) and doxazosin (EjD: UROs 14%, PCPs 10%; ED: UROs 7%, PCPs 12%) than for alfuzosin (EjD: UROs 6%, PCPs 4%; ED: UROs 4%, PCPs 5%). CONCLUSIONS: The results suggest that many PCPs are not using the AUA-SI/IPSS to assess LUTS in their ageing male patients. Both UROs and PCPs appear to be underestimating the prevalence of SD in men with LUTS/BPH relative to prevalence rates reported in large-scale epidemiological studies.

Sexual foreplay incontinence in men with erectile dysfunction after radical prostatectomy: a clinical observation.

Incontinence is a known complication of radical prostatectomy for prostate cancer. Recently, climacturia, or orgasmic incontinence, has been reported after this procedure. Patients have occasionally reported some loss of urine during sexual foreplay, even when general daytime incontinence was not present. A review of questions on this subject was conducted in 45 men to better appreciate how often this occurred. Nine of twenty-four men (38%) with no daytime incontinence stated that they had some incontinence with sexual foreplay. These men involved have related that this causes embarrassment and frustration, with the effect of avoidance of sexual activity. This in turn causes relationship problems. The use of a rubber ring at the base of the penis during foreplay can help relieve this difficulty.

Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction.

Depression and hypogonadism are associated with erectile dysfunction (ED). We evaluated the prevalence of both conditions in men presenting to an ED specialty clinic, and tested whether hypogonadism correlated with the presence of depressive symptoms using a validated questionnaire. From July 2001 to June 2003, 157 men referred to an ED specialty clinic prospectively filled the Center for Epidemiologic Studies Depression Scale (CES-D), the abbreviated International Index of Erectile Function (IIEF-5) and had testosterone serum levels drawn. Median age was 53 (range=21-85 years). Hypogonadism, defined as serum T (testosterone)<300 mg/dl, was present in 36% of patients. This proportion was higher in men over the median age compared to younger patients (45 and 26%, respectively, P=0.002). Overt depression symptoms, defined as a CES-D> or =22, were found in 24% of men. Mean age of men with overt depression was 49.9+/-10.1 years vs 55.1+/-15.8 years for those with CES-D<22 (P=0.02). Hypogonadal men were more likely to have overt depression scores compared to eugonadal counterparts (35 vs 18%, P=0.02). This association was statistically stronger after correcting for age in a multivariate linear model (P=0.005). The relative risk of having overt depression was 1.94 times higher in men with hypogonadal testosterone level (95% confidence interval: 1.13 to 3.7). We conclude that in an ED referral population, symptoms of hypogonadism and depression symptoms are fairly prevalent, and that overt depression symptoms are strongly associated with hypogonadism. Clinicians should consider testosterone measurements in all men with high depression symptom scores.

The impact of formulary replacement of sildenafil by vardenafil at a local VA hospital.

The National Veterans Administration (VA) changed its formulary agent for the treatment of erectile dysfunction from sildenafil to vardenafil in January 2006 for economic reasons. The objective of this study was to assess the impact of this formulary change on the patients at a local VA hospital. All non-formulary requests for sildenafil between January 2006 and September 2006 were reviewed. A total of 169 non-formulary requests were made for sildenafil while 7657 patients filled vardenafil prescriptions. Overall, the formulary change from sildenafil to vardenafil appeared to be well tolerated by the vast majority of patients at this local VA hospital. The substantial cost savings to the VA seem to be justified by the minimal adverse effects on men treated for erectile dysfunction.

Sildenafil reduces bother associated with erectile dysfunction: pooled analysis of five randomized, double-blind trials.

Improvement in bother associated with erectile dysfunction (ED) is an important aspect of successful treatment of ED. Changes in erectile function and the bother associated with ED were assessed in this analysis of pooled data from five 12-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose studies of sildenafil. Men who received sildenafil (n=578, vs placebo, n=550) had significantly greater (least squares mean+/-s.e.) improvement in erectile function (EF) domain scores of the international index of erectile function (IIEF) (10.0+/-0.3 vs 1.0+/-0.3, P<0.0001) and in erection distress scale (EDS) total transformed score (18.8+/-0.8 vs 4.8+/-0.9, P<0.0001). Scores on individual questions of the EDS were 24-65% higher after treatment with sildenafil (vs 8-12%, for placebo). The change in EF domain score correlated positively with the change in total transformed EDS score (0.43, P<0.0001). Successful treatment of ED with sildenafil may reduce the bother associated with ED.

Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead?

A 2003 report by the Institute of Medicine (IOM) surveyed the literature on the benefits and risks of testosterone replacement therapy in older men and identified knowledge gaps and research needs. This review summarises some key studies published since the IOM report. The possible relationship of testosterone to risk of prostate cancer remains a concern; however, no new evidence has emerged to suggest that testosterone replacement therapy increases the risk. Recent studies have demonstrated that hypogonadism in men may be more prevalent than previously thought, is strongly associated with metabolic syndrome, and may be a risk factor for type 2 diabetes and cardiovascular disease. Clinical studies have shown that testosterone replacement therapy in hypogonadal men improves metabolic syndrome indicators and cardiovascular risk factors. Maintaining testosterone concentrations in the normal range has been shown to contribute to bone health, lean muscle mass, and physical and sexual function, suggesting that testosterone replacement therapy may help to prevent frailty in older men. Based on current knowledge, testosterone replacement therapy is unlikely to pose major health risks in patients without prostate cancer and may offer substantial health benefits. Larger, longer-term randomised studies are needed to fully establish the effects of testosterone replacement therapy.

Male hypogonadism. Part I: Epidemiology of hypogonadism.

Male hypogonadism is a frequent and potentially undertreated condition. A number of longitudinal epidemiologic studies, including the Baltimore Longitudinal Study of Aging, the New Mexico Aging Process Study, and the Massachusetts Male Aging Study, have demonstrated age-related increases in the likelihood of developing hypogonadism. In addition to advancing age, increasing body mass index and/or type II diabetes mellitus may be associated with lower circulating androgen levels. Owing to the demographic trends toward increasing population age and life expectancy, together with the emerging pandemic of diabetes and recent trend toward an increasing prevalence of obesity in the United States, clinicians are likely to encounter increasing cases of hypogonadism in the near future.

Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors.

Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n=24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg+tadalafil 20 mg, and dapoxetine 60 mg+sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil, and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated.