Allen D. Seftel

The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. The third Princeton Consensus met November 8 to 10, 2010, and had 2 primary objectives. The first objective focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic work-up. The second objective focused on reevaluation and modification of previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD. The Panels recommendations build on those developed during the first and second Princeton Consensus Conferences, first emphasizing the use of exercise ability and stress testing to ensure that each mans cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED, and second highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.

SEXUAL FUNCTION IN MEN WITH DIABETES TYPE 2: ASSOCIATION WITH GLYCEMIC CONTROL

PURPOSE We evaluated the association of glycemic control with erectile dysfunction in men with diabetes type 2. MATERIALS AND METHODS A convenience sample of men with diabetes type 2 at the Cleveland Veterans Affairs Medical Center completed questions 1 to 5 of the International Index of Erectile Function. The primary outcome measure was erectile function score, calculated as the sum of questions 1 to 5. Details of disease duration, complications, medication use, patient age and level of glycosylated hemoglobin were obtained by reviewing the medical record. RESULTS Mean subject age plus or minus standard deviation was 62.0+/-12.3 years, mean hemoglobin A1c was 8.1%+/-1.9% and mean erectile function score was 16.6+/-5.9 (range 5 to 23). Stratified analysis revealed that mean erectile function score decreased as hemoglobin A1c increased (analysis of variance p = 0.002). The test for linearity was also significant (p = 0.001). There were no statistically significant associations of levels of glycemic control with alpha-blocker, beta-blocker or diuretic use. Bivariate analysis showed a significant correlation of hemoglobin A1c with neuropathy but not with patient age, duration of diabetes, alpha-blockers, beta-blockers or diuretics. Multivariate analysis demonstrated that hemoglobin A1c was an independent predictor of erectile function score (p<0.001) even after adjusting for peripheral neuropathy, which was also an independent predictor (p = 0.023). CONCLUSIONS Our data add to the growing body of literature suggesting that erectile dysfunction correlates with the level of glycemic control. Peripheral neuropathy and hemoglobin A1c but not patient age were independent predictors of erectile dysfunction.

A New Protocol for the Followup of Renal Cell Carcinoma Based on Pathological Stage

There is no consensus concerning which laboratory and imaging studies should be obtained to assess patients after radical nephrectomy for renal cell carcinoma. We retrospectively reviewed 158 patients who underwent radical nephrectomy with a final pathological diagnosis of renal cell carcinoma. Of the patients 21 had node-positive or metastatic disease and 137 had no evidence of metastases at diagnosis. Of the latter group 19 had pathological stage T1N0M0, 82 stage T2N0M0 and 36 stage T3N0M0 (18 stage T3a, 10 stage T3b and 8 stages T3a and b) tumor. Disease recurred in 0%, 14.6% and 52.8% (50%, 44.4% and 75%) of the patients, respectively. The average interval to recurrence was 29.5 months (range 3.5 to 88.8) for patients with stage T2 carcinoma and 22 months (range 3 to 138) for those with stage T3 disease. Based upon our data, followup studies should include a symptom history, serum liver function studies and chest x-rays at defined intervals. Routine use of bone scans and computerized tomography does not appear to be necessary.

SKELETAL FRACTURE ASSOCIATED WITH ANDROGEN SUPPRESSION INDUCED OSTEOPOROSIS: THE CLINICAL INCIDENCE AND RISK FACTORS FOR PATIENTS WITH PROSTATE CANCER

PURPOSE Limited information exists regarding the long-term risk of skeletal fracture in men on androgen suppression for prostate cancer. In addition, the clinical risk factors predisposing them to skeletal fracture are incompletely defined. We define the long-term risk and clinical risk factors for skeletal fracture in patients with prostate cancer on chronic androgen suppression. MATERIALS AND METHODS A total of 181 consecutive patients with prostate cancer on androgen suppression therapy were evaluated. The primary end point was skeletal fracture. Comprehensive demographic information was gathered, and univariate and multivariate analyses were performed to identify associations with skeletal fracture. RESULTS The proportion of patients who had survived fracture-free at 5 and 10 years on androgen suppression therapy was 96% and 80%, respectively. The black race (p = 0.009) and increased body mass index (p = 0.024) were identified as protective against androgen suppression associated skeletal fractures. A significant correlation was identified between the duration of androgen suppression and risk of skeletal fracture (p = 0.003). CONCLUSIONS Patients with prostate cancer treated with androgen suppression are at risk for skeletal fracture, and risk increases with the duration of therapy. Slender white men are at greatest risk. Conversely, black men and those with body mass indexes greater than normal (greater than 25 kg/m(2)) are at minimal risk despite a prolonged duration (10 years) of androgen suppression.

Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through inos or enos

OBJECTIVES We hypothesized that advanced glycation end product (AGE) formation contributes to erectile dysfunction (ED) by quenching nitric oxide. Our first goal was to identify the specific AGE pentosidine in the diabetic human penis. Because AGE-mediated effects may involve inducible nitric oxide synthase (iNOS), we performed immunohistochemical and Western blot analysis of diabetic and nondiabetic human penile tissue for iNOS. Finally, because AGEs may act intracellularly to affect proteins, we set out to identify endothelial NOS (eNOS) in the human penis as an initial step in examining a possible intracellular interaction between eNOS and AGEs. METHODS We performed high-performance liquid chromatographic analysis of diabetic human penile corpus cavernosum and serum for pentosidine and performed immunohistochemical, electron microscopic (EM), and Western blot analysis of the diabetic and nondiabetic penile corpus cavernosum and tunica for pyrraline, iNOS, and eNOS (and neural NOS [nNOS] for comparative purposes) via standard methods. RESULTS We found a significant elevation of pentosidine in the penile tissue but not the serum of diabetic patients (average age 55.6 +/- 2.3 years) compared with that of nondiabetic patients (average age 61.8 +/- 3.6 years). Pentosidine was 117.06 +/- 9.19 pmol/mg collagen in the diabetic tunica versus 77.58 +/- 5.5 pmol/mg collagen in the nondiabetic tunica (P < 0.01) and 74.58 +/- 8.49 pmol/mg collagen in the diabetic corpus cavernosum versus 46.59 +/- 2.53 pmol/mg collagen in the nondiabetic corpus cavernosum (P < 0.01), suggesting a tissue-specific effect of the AGEs. We localized the site of deposition of the specific AGE pyrraline to the human penile tunica and the penile corpus cavernosum collagen. Immunohistochemical and EM analysis localized eNOS and iNOS to the cavernosal endothelium and smooth muscle. Western blot analysis in 6 patients revealed the following: iNOS, but no eNOS, in penile tissue from 1 insulin-dependent diabetic man; eNOS only in 1 man after radical prostatectomy; both eNOS and iNOS in 2 men with Peyronies disease, as well as in 2 other men with impotence and hypertension. Finally, the specific iNOS inhibitor PNU-19451A significantly augmented relaxation of precontracted human cavernosal tissue, from 64.7% +/- 5.58 to 80.03% +/- 4.55 at 10 microM acetylcholine and 65.06% +/- 2.84 to 86.16% +/- 3.96 at 0.1 mM acetylcholine (n = 4, P < 0.002 and P < 0.02, respectively). CONCLUSIONS AGEs are elevated in diabetic human penile tissue, but not in serum, and are localized to the collagen of the penile tunica and corpus cavernosum. We identified eNOS and iNOS in the human penile cavernosal smooth muscle and endothelium. The augmentation of cavernosal relaxation with a specific iNOS inhibitor, combined with the identification of iNOS protein, but not eNOS, in a patient with severe diabetes and ED, allows for speculation of a pathophysiologic mechanism for AGE-mediated ED via upregulation of iNOS and downregulation of eNOS. These data provide further insight into the mechanisms of advanced glycation end product-mediated ED and provide a foundation for further study.

Sexual Activity and Cardiovascular Disease A Scientific Statement From the American Heart Association

Sexual activity is an important component of patient and partner quality of life for men and women with cardiovascular disease (CVD), including many elderly patients.1 Decreased sexual activity and function are common in patients with CVD and are often interrelated to anxiety and depression.2,3 The intent of this American Heart Association Scientific Statement is to synthesize and summarize data relevant to sexual activity and heart disease in order to provide recommendations and foster physician and other healthcare professional communication with patients about sexual activity. Recommendations in this document are based on published studies, the Princeton Consensus Panel,4,5 the 36th Bethesda Conference,6–10 European Society of Cardiology recommendations on physical activity and sports participation for patients with CVD,11–13 practice guidelines from the American College of Cardiology/American Heart Association14–16 and other organizations,17 and the multidisciplinary expertise of the writing group. The classification of recommendations in this document are based on established ACCF/AHA criteria (Table). View this table: Table. Applying Classification of Recommendation and Level of Evidence Numerous studies have examined the cardiovascular and neuroendocrine response to sexual arousal and intercourse, with most assessing male physiological responses during heterosexual vaginal intercourse.18–24 During foreplay, systolic and diastolic systemic arterial blood pressure and heart rate increase mildly, with more modest increases occurring transiently during sexual arousal. The greatest increases occur during the 10 to 15 seconds of orgasm, with a rapid return to baseline systemic blood pressure and heart rate thereafter. Men and women have similar neuroendocrine, blood pressure, and heart rate responses to sexual activity.24,25 Studies conducted primarily in young married men showed that sexual activity with a persons usual partner is comparable to mild to moderate physical activity in the range of 3 to …

Small cell carcinoma of the genitourinary tract : an immunohistochemical, electron microscopic and clinicopathological study

We examined 13 cases of small cell carcinoma of the genitourinary tract to evaluate and compare the immunocytochemical and ultrastructural features as well as the clinicopathological behavior. Immunohistochemical stains revealed that neuron specific enolase and chromogranin showed differences in staining between the bladder and prostate, as well as between the small cell and adenocarcinomatous components of the prostate. Also, synaptophysin was negative over-all in 12 of 13 cases. Epithelial membrane antigen, carcinoembryonic antigen and keratin showed strong focal positivity within the small cell component. Electron microscopy was performed in 4 cases, with 3 demonstrating neurosecretory granules. Clinically, 6 of the 7 patients with adenocarcinoma/small cell carcinoma of the prostate did poorly, all with a survival of 15 months or less. Of 5 patients with transitional cell/small cell carcinoma of the bladder 2 fared better (both had no evidence of disease at 12 months and 11 years, respectively). Based upon the immunostaining and electron microscopic findings, small cell carcinoma of the genitourinary tract is heterogeneous in appearance and, therefore, may arise from a multipotential cell of origin. This cell of origin may be organ-specific, as demonstrated by the variability in staining characteristics among the prostate, bladder and kidney, as well as by the differences in the clinical behavior of these malignancies. Small cell carcinoma of the prostate has a poor prognosis, while small cell carcinoma of the bladder may portend a better prognosis if diagnosed at an early stage.

Distribution of Chronic Prostatitis in Radical Prostatectomy Specimens With Up-Regulation of BCL-2 in Areas of Inflammation

PURPOSE We examined the anatomical relationship of chronic prostatitis with prostate cancer and benign prostatic hyperplasia (BPH) based on the hypothesis that there may be an association of prostatitis with these other entities that may involve up-regulation of bcl-2. MATERIALS AND METHODS We examined 40 whole mount radical prostatectomy specimens for the presence and distribution of chronic inflammatory infiltrate. Immunostaining for bcl-2 was done in 10 cases. RESULTS Chronic prostatitis was identified in all 40 cases with peripheral zone inflammation in 95% and transition zone inflammation in 87.5%. In all cases of transition zone inflammation the infiltrate was noted within and/or around BPH. Inflammatory infiltrate was microscopically associated with prostate cancer in 23 of the 40 cases (57.5%). In these 23 cases, there was no association of inflammation with Gleason score, preoperative prostate specific antigen, positive margins, or seminal vesicle invasion. Patients with BPH unassociated with prostatitis had significantly smaller prostate weight (median 32 gm.) and were younger (mean age 54.4 years) than those with BPH associated with prostatitis (median weight 40 gm. and mean age 61.4 years, p <0.05). Bcl-2 staining was intensified in benign glands within areas of prostatitis in all 10 cases examined. CONCLUSIONS Chronic prostatitis is a common finding in radical prostatectomy specimens. Inflammation was associated with BPH and cancer but had a greater tendency to be associated with BPH. Bcl-2 was prominently expressed in areas of prostatitis. Our findings indirectly support a potential role for prostatitis in the pathogenesis of BPH.

Association of Sexual Dysfunction With Lower Urinary Tract Symptoms of BPH and BPH Medical Therapies: Results From the BPH Registry

OBJECTIVES The severity of lower urinary tract symptoms (LUTS) has correlated with erectile dysfunction (ED) and ejaculatory dysfunction (EjD) in large-scale epidemiologic studies. ED and EjD are also side effects of some medical therapies for LUTS suggestive of benign prostatic hyperplasia (LUTS/BPH). These relationships were examined in a physician office-based population of men enrolled in the BPH Registry. METHODS Enrolled men with LUTS/BPH who completed the International Prostate Symptom Score (IPSS), IPSS bother question, 5-item International Index of Erectile Function, and the 3 ejaculatory function items of the Male Sexual Health Questionnaire-EjD short form at baseline were eligible. The relationship between sexual dysfunction and LUTS/BPH and BPH medical therapies were examined using multivariate analyses. RESULTS Of 6924 men enrolled, 5042 (mean age 65 years) completed all 4 baseline assessments. Of 3084 sexually active men, age, total IPSS, IPSS bother score, hypertension, diabetes, and black race/ethnicity were independent predictors of both ED and EjD (all P < .05). For the subset of 1362 men receiving BPH medical therapy, a significant association (P < .0001) was demonstrated for ED and EjD with specific BPH medical therapies. The alpha(1A)-subtype nonsuperselective quinazoline alpha(1)-blockers alfuzosin, doxazosin, and terazosin appeared to be associated with better ejaculatory function than were the alpha(1A)-subtype superselective sulfonamide alpha(1)-blocker tamsulosin, 5alpha-reductase inhibitors, and alpha(1)-blocker plus 5alpha-reductase inhibitor combination therapy. CONCLUSIONS These results have provided additional evidence of the link between LUTS/BPH and sexual dysfunction in aging men and support clinical trial results indicating different rates of sexual side effects for BPH medical therapies.

Peyronie’s Disease: AUA Guideline

PURPOSE The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronies disease. MATERIALS AND METHODS A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. RESULTS The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence. CONCLUSIONS There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patients history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.