James M. Hotaling

ERECTILE DYSFUNCTION AFTER RADICAL PROSTATECTOMY: HEMODYNAMIC PROFILES AND THEIR CORRELATION WITH THE RECOVERY OF ERECTILE FUNCTION

PURPOSE Despite the advent of nerve sparing radical prostatectomy some men experience erectile dysfunction. Many of these men have vasculogenic erectile impairment in the form of arterial insufficiency or venous leakage. Recent data imply that early postoperative injection therapy may decrease the rate of erectile dysfunction. We defined hemodynamic patterns in patients who underwent bilateral nerve sparing radical prostatectomy to assess the chronology of venous leakage development and explore the correlation of hemodynamic profiles with the return of functional erection 12 months postoperatively. MATERIALS AND METHODS Patients with excellent preoperative erectile function who underwent bilateral nerve sparing surgery and had no pharmacological support for erectile dysfunction in the initial 12 months after surgery received vascular evaluation at presentation. Vascular evaluation involved cavernosometry or penile ultrasonography. Patients were then interviewed again at least 12 months postoperatively to assess the ability to achieve sexual intercourse. RESULTS Our study group comprised 96 men with a mean age plus or minus standard deviation of 54 +/- 12 years who met all inclusion criteria. All patients had pathologically proved organ confined disease. Mean time to the initial postoperative presentation was 6 +/- 5 months. Patients were divided into 4 groups according to the time of vascular studies postoperatively, namely less than 4 to 8, 9 to 12 and greater than 12 months. Normal vascular status, arterial insufficiency and venous leakage were diagnosed in 35%, 59% and 26% of the group, respectively. No difference in the incidence of arterial insufficiency was noted in the 4 time groups. Time postoperatively was significantly associated with the incidence of venous leakage (14% at less than 4 months and 35% at between 9 and 12). In regard to the correlation of the vascular diagnosis with the return to functional erection 47% of the normal, 31% of the arteriogenic and 9% of the venous leakage group achieved sexual intercourse 12 months postoperatively. CONCLUSIONS These data imply that the longer the duration of erectile dysfunction after radical prostatectomy, the greater the risk of venous leakage. Furthermore, it appears that the prognosis for the return of functional erection is worst when venous leakage is present.

Analysis of Diagnostic Angiography and Angioembolization in the Acute Management of Renal Trauma Using a National Data Set

PURPOSE To our knowledge data on diagnostic angiography and angioembolization after renal trauma have been limited to single institution series with small numbers. We used the National Trauma Data Bank® to investigate national patterns of diagnostic angiography and angioembolization after blunt and penetrating renal trauma. MATERIALS AND METHODS All renal injuries treated between 2002 and 2007 were identified in the National Trauma Data Bank by Abbreviated Injury Scale codes and converted to American Association for the Surgery of Trauma renal injury grades. Diagnostic angiography and angioembolization were identified by ICD-9 codes and examined. Initial angioembolization was considered a failure if subsequent therapy was needed. Repeat diagnostic angiography was not considered a failure. RESULTS A total of 9,002 renal injuries were available for analysis. A total of 165 patients (2%) underwent diagnostic angiography after renal injury, including 77 (47%) who underwent concomitant angioembolization. Of the patients 78% sustained grade III-V renal injuries. Of the 77 patients with initial angioembolization 68 required successive therapy. Repeat angioembolization was the most common management choice (29% of patients). Secondary angioembolization was durable during the index hospitalization with success in 35 of 36 cases. Successive therapy was required after initial angioembolization for all grade IV and V renal injuries in 48 patients. The overall renal salvage rate was 92%, including 88% for grade IV and V injuries. CONCLUSIONS Successive therapy is common after initial management of renal injury by angioembolization. Close observation is highly recommended after initial angioembolization for grade IV-V renal injuries. National agreement on the use of diagnostic angiography and angioembolization is needed since these procedures may be overused after grade I-III renal injuries.

Male infertility: a risk factor for testicular cancer

Male infertility lies at the crossroads of genetic determinants and environmental effects. Although the exact genetic mechanisms of male infertility are still unclear, this disorder is associated with a host of medical diseases, including testicular cancer. Testicular dysgenesis syndrome, the Hiwi protein and chromosome 12 aneuploidy, DNA mismatch repair, and Y-chromosome instability have been postulated as possible connections between male infertility and testicular germ cell tumor (TGCT). The advent of assisted reproductive technology has allowed men to bypass evaluation by a urologist with expertise in infertility at a time when semen quality seems to be decreasing in parallel with an increasing incidence of TGCT in industrialized nations. Advances in epigenetics, the sequencing of the human genome and maturation of large datasets from countries with centralized medical records are heralding a new era of genetic medicine in this field. The exquisite sensitivity of the germinal epithelium to changes in the external environment and the internal metabolic profile present an excellent opportunity to explore the interaction between infertility and TGCT. The elucidation of the pathways underlying this association will enable development of appropriate tests that will identify men susceptible to development of TGCT and other testicular pathologies.

Comparative analysis of three sperm DNA damage assays and sperm nuclear protein content in couples undergoing assisted reproduction treatment

STUDY QUESTION Is there an association between sperm DNA damage, measured by three different assays, sperm nuclear protein content and clinical outcomes in assisted reproduction treatment (ART)? SUMMARY ANSWER Sperm DNA damage measured by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) and the Comet assay were significantly associated with ART outcomes in our single institution study. WHAT IS KNOWN ALREADY Abnormal protamine expression is known to be associated with sperm DNA damage and male infertility. A number of studies have shown a significant relationship between sperm DNA damage and ART outcomes. To date, there are no large studies providing direct comparisons of DNA damage tests within the same study population. Thus, the prognostic value for each method remains unknown. STUDY DESIGN, SIZE, DURATION Cross-sectional study of 238 men from infertile couples undergoing ART at the University Center for Reproductive Medicine, Utah, USA, between April 2011 and March 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS Sperm from men undergoing ART were tested for DNA damage using the alkaline Comet assay, TUNEL and flow cytometric chromatin evaluation (FCCE) assays. Histone retention was analysed using the aniline blue staining method, whereas protamine content (proteins P1 and P2) and ratio were analysed using acid urea gel electrophoresis. The prognostic value of each sperm DNA test to predict clinical pregnancy was calculated. MAIN RESULTS AND THE ROLE OF CHANCE Histone retention was associated with sperm DNA damage (P < 0.001), reduced embryo quality (P = 0.005) and clinical pregnancies (P < 0.001). The mean percentage of sperm with DNA damage was significantly higher in sperm from non-pregnant couples compared with that from pregnant couples, as measured by TUNEL assay (15.04 ± 1.16% versus 8.79 ± 0.56%; P < 0.001) and alkaline Comet assay (72.79 ± 2.49% versus 55.86 ± 2.29%; P < 0.001). There was no association between clinical pregnancies and DNA fragmentation index measured by FCCE (12.97 ± 1.46 versus 14.93 ± 1.65; P = 0.379). Of the protamine parameters analysed, only the P1/P2 ratio was associated with sperm count (P = 0.013), mens age (P = 0.037), maturity (P = 0.049) and blastocyst quality (P = 0.012). Histone retention and sperm DNA damage measured by Comet and TUNEL assays were associated with fertilization rate (P < 0.05), embryo quality (P < 0.05) and implantation rate (P < 0.05). LIMITATIONS, REASONS FOR CAUTION A potential drawback of this study is that it is cross-sectional. Generally in such studies there is more than one variable that could cause the effect. Analysing sperm is one part of the equation; there are also a number of female factors that have the potential to influence ART outcomes. Therefore, given the large and well-established role of female factors in infertility, normal sperm DNA integrity and protamination do not necessarily ensure clinical pregnancy in ART. Thus, female factors can reduce the prognostic value of sperm DNA tests. Further, our use of native semen instead of prepared sperm may have iatrogenically increased the DNA damage. WIDER IMPLICATIONS OF THE FINDINGS Alteration in sperm nuclear protein affects sperm DNA integrity. Further, with the current dataset, TUNEL and Comet assays appeared more predictive of ART success than FCCE. STUDY FUNDING/COMPETING INTEREST(S) No personal or direct financial support has been received for any of this work. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

Clinical genetic testing for male factor infertility: current applications and future directions

Spermatogenesis involves the aggregated action of up to 2300 genes, any of which, could, potentially, provide targets for diagnostic tests of male factor infertility. Contrary to the previously proposed common variant hypothesis for common diseases such as male infertility, genome‐wide association studies and targeted gene sequencing in cohorts of infertile men have identified only a few gene polymorphisms that are associated with male infertility. Unfortunately, the search for genetic variants associated with male infertility is further hampered by the lack of viable animal models of human spermatogenesis, difficulty in robustly phenotyping infertile men and the complexity of pedigree studies in male factor infertility. In this review, we describe basic genetic principles involved in understanding the genetic basis of male infertility and examine the utility and proper clinical use of the proven genetic assays of male factor infertility, specifically Y chromosome microdeletions, chromosomal translocations, karyotype, cystic fibrosis transmembrane conductance regulator mutation analysis and sperm genetic tests. Unfortunately, these tests are only able to diagnose the cause of about 20% of male factor infertility. The remainder of the review will be devoted to examining novel tests and diagnostic tools that have the potential to explain the other 80% of male factor infertility that is currently classified as idiopathic. Those tests include epigenetic analysis of the spermatozoa and the evaluation of rare genetic variants and copy number variations in patients. Success in advancing to the implementation of such areas is not only dependent on technological advances in the laboratory, but also improved phenotyping in the clinic.

Predictors of Upper Tract Urothelial Cell Carcinoma After Primary Bladder Cancer: A Population Based Analysis

PURPOSE Upper tract tumors occur in 2% to 7% of patients after primary bladder cancer, making surveillance upper tract imaging part of bladder cancer management. We determined the cumulative incidence of secondary upper tract tumor development after primary bladder cancer and risk factors for secondary upper tract tumors using contemporary population based data. MATERIALS AND METHODS We identified patients with bladder cancer in the Surveillance, Epidemiology, and End Results cancer registry from 1988 to 2003. All subsequent cases of upper tract tumors were ascertained. Multivariate Cox survival analysis was performed to evaluate risk factors for secondary upper tract tumors after adjusting for age, race, gender, stage, grade, tumor location, surgical management, year of diagnosis and tumor registry. RESULTS Of 99,338 patients with bladder cancer upper tract tumors developed in 768 (0.8%). The median time to secondary upper tract tumors was 33 months. Of upper tract tumors 71% developed within 5 years of bladder cancer diagnosis and only 6% developed more than 10 years after diagnosis. On multivariate analysis high grade (HR 2.16, 95% CI 1.71-2.74) and nonmuscle invasive disease (Ta, T1) (HR 1.16, 95% CI 0.97-1.39) were predictive of upper tract tumor recurrence. Upper tract disease was more likely to develop in patients with tumors at the trigone/ureteral orifice (HR 1.76, 95% CI 1.48-2.09). CONCLUSIONS Upper tract tumors developed in 0.8% of patients with bladder cancer. Although late cases occurred, upper tract tumors developed in the majority of cases within 3 years. Pathological factors such as tumor grade, stage and location were predictive of upper tract recurrence. These findings may be useful for tailoring surveillance protocols in patients with bladder cancer.

The relationship between isolated teratozoospermia and clinical pregnancy after in vitro fertilization with or without intracytoplasmic sperm injection: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis of data from the literature from the years 1986 to 2009 using teratozoospermia and fertilization or IVF or in vitro fertilization as the keywords. A total of 31 studies were identified, and 4 met the inclusion criteria. Isolated teratozoospermia was not associated with a statistically significantly decreased probability of pregnancy with assisted reproduction.

Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization

OBJECTIVE To assess the effects of both male and female body mass index (BMI), individually and combined, on IVF outcomes. DESIGN Prospective cohort study. SETTING University fertility center. PATIENT(S) All couples undergoing first fresh IVF cycles, 2005-2010, for whom male and female weight and height information were available (n = 721 couples). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Embryologic parameters, clinical pregnancy, and live birth incidence. RESULT(S) The average male BMI among the study population was 27.5 ± 4.8 kg/m(2) (range, 17.3-49.3 kg/m(2)), while the average female BMI (n = 721) was 25.2 ± 5.9 kg/m(2) (range, 16.2-50.7 kg/m(2)). Neither male nor female overweight (25-29.9 kg/m(2)), class I obese (30-34.9 kg/m(2)), or class II/III obese (≥35 kg/m(2)) status was significantly associated with fertilization rate, embryo score, or incidence of pregnancy or live birth compared with normal weight (18.5-24.9 kg/m(2)) status after adjusting for male and female age, partner BMI, and parity. Similar null findings were found between combined couple BMI categories and IVF success. CONCLUSION(S) Our findings support the notion that weight status does not influence fecundity among couples undergoing infertility treatment. Given the limited and conflicting research on BMI and pregnancy success among IVF couples, further research augmented to include other adiposity measures is needed.

Effect of Collecting Duct Histology on Renal Cell Cancer Outcome

PURPOSE Collecting duct renal cell carcinoma is a rare entity. Recent surgical series of the condition showed conflicting results. We used an American population based data set to compare the survival experience of patients with collecting duct vs clear cell renal cell carcinoma. MATERIALS AND METHODS Cases of collecting duct and clear cell renal cell carcinoma were identified in the Surveillance, Epidemiology and End Results program (2001 to 2005). Demographic and pathological characteristics at diagnosis were compared. Differences in disease specific survival were compared with univariate and multivariate Cox regression analysis. RESULTS A total of 160 collecting duct renal cell carcinoma cases were present in the database from 2001 to 2005. In that time 33,252 clear cell renal cell carcinoma cases were diagnosed. Collecting duct renal cell carcinoma was more common in black than in white patients (23% vs 9%, p <0.001). Collecting duct renal cell carcinoma was more commonly T3+ than T2/T1 (33% vs 18%, p <0.001) and metastatic than regional/local (28% vs 17%, p = 0.001). Nephrectomy rates were similar (84% and 78%, p = 0.06). The 3-year disease specific survival rate was 58% and 79% for collecting duct and clear cell renal cell carcinoma, respectively. On multivariate analysis there was an increased mortality risk in patients with collecting duct vs clear cell renal cell carcinoma (HR 2.42, 95% CI 1.72-3.39, p = 0.001). CONCLUSIONS Compared to patients with clear cell renal cell carcinoma those with collecting duct renal cell carcinoma have higher stage and are more often black. Even after adjusting for demographic, surgical and pathological factors disease specific survival is significantly worse in patients with collecting duct rather than clear cell renal cell carcinoma. Further research into the biology of this rare tumor is required to explain these results.

Genetics of Male Infertility

Genetics play an important role in the evaluation of the infertile male. The current limitations of classifying the genetic contribution to male infertility and the importance of phenotyping men are discussed, and the core concepts necessary to interpret most genetic studies are reviewed. The current genetic assays used clinically are discussed in detail. The use and interpretation of the cystic fibrosis transmembrane receptor assay are examined in the context of men with clinical bilateral absence of the vas deferens, a karyotype and Klinefelter syndrome, and Y chromosome microdeletions. The role of hormones and epigenetics in evaluating the genetic reproductive potential of men is discussed briefly. A summary of what the field might look like in 2034 is presented.