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.

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.

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.

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.

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.

Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents.

Male hypogonadism is associated with potentially distressing adverse effects on diverse organs and tissues. These include sexual dysfunction, particularly diminished libido, as well as mood disturbances, reduced lean body mass, and increased adipose-tissue mass. A wide range of effective and well-tolerated options exists. These include relatively noninvasive therapies, such as testosterone (T) gels and T patches; slightly more invasive treatments, such as the T buccal system; and invasive therapies, such as intramuscular T injections and subcutaneous depot implants (T pellets). Testosterone replacement therapy (TRT) can be individualized to enhance patient health and well-being. Screening and ongoing monitoring are necessary to ensure both the efficacy and safety of TRT, particularly prostate safety. Investigational agents, including selective androgen receptor modulators, may offer new pharmacodynamic and/or pharmacokinetic properties that enhance outcomes of TRT.

Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia.

We evaluated the effects of extended-release alfuzosin HCl 10 mg once daily (q.d.) on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). In a randomized, double-blind, placebo-controlled study of men aged > or = 50 years, after a 28-day placebo run-in period, patients were randomized to receive alfuzosin 10 mg q.d. or matching placebo for 28 days. The mean change from baseline (day 1) in sexual function on day 29 was assessed using the Danish Prostate Symptom Score Sex (DAN-PSSsex) questionnaire. A total of 372 patients were randomized to receive alfuzosin (n=186) or placebo (n=186), with 355 completing the study. At baseline, 64% of the patients reported erectile dysfunction (ED) and 63% reported ejaculatory dysfunction (EjD). For the 320 patients who completed the DAN-PSSsex, alfuzosin treatment was associated with a significant improvement in the mean change from baseline in erectile function on day 29 compared with placebo (P=0.02). No significant difference was observed between the two treatment groups in the mean change from baseline in ejaculatory function on day 29. For patients with ED at baseline, a marginal improvement in erectile function was demonstrated with alfuzosin treatment (P=0.09 vs placebo). For patients with EjD at baseline, the mean change from baseline in ejaculatory function with alfuzosin was comparable to that with placebo. Dizziness was the most common adverse event with alfuzosin treatment (5 vs 0% with placebo), with other adverse events reported with comparable frequency in both treatment groups. After 1 month of treatment, alfuzosin 10 mg q.d. significantly improved erectile function in men with lower urinary tract symptoms/ benign prostatic hypertrophy and had no adverse effect on ejaculatory function.

Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications.

In a large-scale epidemiology study, 50% of aging men reported erectile dysfunction (ED) or ejaculatory dysfunction (EjD), with lower urinary tract symptoms (LUTS) an independent risk factor for each of these conditions. In light of the shift from urologists (UROs) to primary care/internal medicine physicians (PCPs) for the initial management of men with LUTS associated with benign prostatic hyperplasia (BPH), a survey was conducted to assess the perceptions of UROs and PCPs regarding sexual dysfunction (SD) in men with LUTS/BPH and the effects of BPH treatments (alpha(1)-adrenergic receptor antagonists (alpha-blockers) and 5alpha-reductase inhibitors (5ARIs)) on sexual function. The survey was mailed to 7500 UROs and 2500 PCPs, with 1275 (13%) surveys returned (1087 by UROs, 177 by PCPs and 11 by other specialty). Alpha-blocker monotherapy was the most common medication prescribed by both UROs (56%) and PCPs (47%). UROs estimated that 19% of their patients with LUTS/BPH experienced SD owing to their symptoms compared with the estimate of 27% by PCPs. UROs estimated that 19% of their patients experienced SD owing to their BPH medication compared with the PCP estimate of 24%. The incidence of EjD owing to BPH medications estimated by UROs (32%) was higher than that estimated by PCPs (22%); the rate of ED estimated by PCPs (34%) was higher than that estimated by UROs (23%). UROs were more aware than PCPs of the specific sexual side effects caused by alpha-blockers versus 5ARIs. These results suggest that physicians are underestimating the prevalence of SD in men with LUTS/BPH. As men with LUTS/BPH are at increased risk for SD, physicians should be especially cognizant of BPH treatment-related sexual side effects.

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.

Semiquantitative imaging measurement of baseline and vasomodulated normal prostatic blood flow using sildenafil.

The physiologic variability of blood flow to the prostate has not been studied until this time. We report the vasoactive effects of sildenafil and phenylephrine on blood flow of the normal prostate. Sildenafil increases prostate blood flow by approximately 75% and phenylephrine reduces the flow incrementally. Administration of these drugs with dynamic contrast-enhanced magnetic resonance imaging may improve the diagnosis of cancerous tissue because according to the literature, tumor angiogenic vessels lack the vasoactive physiologic response of the normal tissue.

Doppler evaluation of erectile dysfunction - part 1.

Erectile dysfunction (ED) is the consistent inability to achieve and maintain an erection sufficient for satisfactory sexual activity. Erectile dysfunction affects as many as 30 million men in America, with an increasing prevalence with age. Erectile dysfunction is secondary to organic, psychogenic and combined causes. The first part of this review article describes the guidelines for evaluation and treatment plans for men with ED. It also describes the normal sonographic anatomy of the penis, sonographic technique for evaluation of ED and the normal phases of erection.

Doppler evaluation of erectile dysfunction - part 2.

Doppler evaluation in erectile dysfunction (ED) has a significant role in determining the cause of ED. The advantages of penile Doppler and pharmacologic duplex ultrasonography include objective, minimally invasive evaluation of penile hemodynamics at a relatively low cost. Arteriogenic ED may be secondary to peripheral vascular disease and diabetes, or may be seen in association with coronary artery disease. Various parameters, such as diameter of the cavernosal artery, peak systolic flow velocity, degree of arterial dilatation and acceleration time, have been suggested for the diagnosis of arteriogenic ED, but peak systolic flow velocity is the most accurate indicator of arterial disease. This second part of the review article describes the various causes of ED and the interpretation and evaluation of color flow Doppler examination in ED.

Male hypogonadism. Part II: etiology, pathophysiology, and diagnosis.

Male hypogonadism has a multifactorial etiology that includes genetic conditions, anatomic abnormalities, infection, tumor, and injury. Defects in the hypothalamic-pituitary-gonadal axis may also result from type II diabetes mellitus and treatment with a range of medications. Circulating testosterone levels have been associated with sexual function, cognitive function, and body composition. Apart from reduced levels of testosterone, clinical hallmarks of hypogonadism include absence or regression of secondary sex characteristics, reduced fertility (oligospermia, azoospermia), anemia, muscle wasting, reduced bone mass (and bone mineral density), and/or abdominal adiposity. Some patients, particularly those with partial androgen deficiency of the aging male, also experience sexual dysfunction, reduced sense of vitality, depressed mood, increased irritability, difficulty concentrating, and/or hot flushes in certain cases of acute onset. As many patients with male hypogonadism-like patients with erectile dysfunction-do not seek medical attention, it is important for clinicians to be acquainted with the signs and symptoms of hypogonadism, and to conduct appropriate laboratory testing and other assessments to determine the causes and inform the treatment of this condition.

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.

Penile fracture with isolated corpus spongiosum injury.

Penile fractures are classically described as presenting with rapid detumescence of an erection associated with blunt trauma. This clinical finding is due to a tear in the tunica albuginea surrounding the corpora cavernosum. We, however, present the case of a patient who presented with a 'classical' penile fracture but was found on surgical exploration to only have an isolated corpus spongiosum injury.

Predicting hypogonadism in men based upon age, presence of erectile dysfunction, and depression.

Hypogonadism, a disorder associated with aging, can cause significant morbidity. As clinical manifestations of hypogonadism can be subtle, the challenge and the burden of diagnosis remain the responsibility of the clinician. Four different analytic methods were used to predict hypogonadism in men based upon age, the presence of erectile dysfunction (ED) and depression. 218 men were classified by age, serum testosterone level, the presence of ED and depression. Depression was determined by the Center for Epidemiologic Studies Depression Scale (CES-D). ED was assessed by the Sexual Health Inventory for Men (SHIM). Hypogonadism was defined as a serum testosterone level <300 ng/dl. An artificial neural network (ANN) was programmed and trained to predict hypogonadism based upon age, SHIM, and CES-D scores. Subject data was randomly partitioned into a training set of 148 (67.9%) and a test set of 70 (32.1%). The ANN processed the test set only after the training was complete. The discrete predicted binary output was set to (0) if testosterone level was <300 ng/dl or (1) if >300 ng/dl. The data was also analyzed by standard logistic regression (LR), linear and quadratic discriminant function analysis (LDFA and QDFA, respectively). Reverse regression (RR) analysis evaluated the statistical significance of each risk factor. The ANN can accurately predict hypogonadism in men based upon age, the presence of ED, and depression (receiver-operating characteristic=0.725). A four hidden node network was found to have the highest accuracy. RR revealed the depression index score to be most significant variable (P=0.0019), followed by SHIM score (P=0.00602), and then by age (P=0.015). Hypogonadism can be predicated by an ANN using the input factors of age, ED, and depression. This model can help clinicians assess the need for endocrinologic evaluation in men.

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.

Multi-institutional outcome study on the efficacy of closed-suction drainage of the scrotum in three-piece inflatable penile prosthesis surgery.

Infection is a devastating complication of penile prosthesis surgery that occurs in approximately 2-5% of all primary inflatable penile primary implants in most series. Prevention of hematoma and swelling with closed-suction drains has been shown not to increase infection rate and yield an earlier recovery time. Despite the intuitive advantages of short-term closed-suction drainage in reducing the incidence of postoperative scrotal swelling and associated adverse effects, many urologists are reluctant to drain the scrotum because of a theoretical risk of introducing an infection. In conclusion, this study was undertaken to evaluate the incidence of infection in three-piece penile prosthesis surgery with scrotal closed-suction drainage. A retrospective review of 425 consecutive primary three-piece penile prosthesis implantations was performed at three institutions in New Jersey, Ohio, and Arkansas from 1998 to 2002. Following the prosthesis insertion, 10 French Round Blake (Johnson & Johnson) or, in a few cases, 10 French Jackson Pratt, closed-suction drains were placed in each patient for less than 24 h. All subjects received standard perioperative antibiotic coverage. Average age at implant was 62 y (range 24-92 y). Operative time (incision to skin closure) was less than 60 min in the vast majority of cases. There were a total of 14 (3.3%) infections and three hematomas (0.7%) during an average 18-month follow-up period. In conclusion, this investigation revealed that closed-suction drainage of the scrotum for approximately 12-24 h following three-piece inflatable penile prosthesis surgery does not result in increased infection rate and is associated with a very low incidence of postoperative hematoma formation, swelling, and ecchymosis.

A three-part study to investigate the incidence and potential etiologies of tadalafil-associated back pain or myalgia.

The potential mechanisms underlying back pain and/or myalgia experienced by men taking tadalafil were investigated. An integrated analysis of 10 placebo-controlled tadalafil clinical trials (N=1846) showed that the incidence of back pain and/or myalgia was 9.4% in patients receiving tadalafil 10 mg (N=394), 8.3% in patients receiving tadalafil 20 mg (N=883) and 3.7% in placebo-treated patients (N=569). One (0.3%) patient receiving tadalafil 10 mg, six (0.7%) patients receiving tadalafil 20 mg, and no patients receiving placebo discontinued treatment due to back pain and/or myalgia. In a prospective study in healthy volunteers, no substantial changes were observed in laboratory markers indicative of inflammation or muscle damage, and tadalafil did not affect renal plasma flow nor produce lumbar or gluteal myositis by positron emission tomography scan or magnetic resonance imaging. Although the mechanism of back pain and/or myalgia remains unknown, these events appear to be self-limiting and a general effect of phosphodiesterase 5 inhibition.