One size does not fit all: variations by ethnicity in demographic characteristics of men seeking fertility treatment across North America.

OBJECTIVE: To compare racial differences in male fertility history and treatment. DESIGN: Retrospective review of prospectively collected data. SETTING: North American reproductive urology centers. PATIENT(S): Males undergoing urologist fertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and reproductive Andrology Research Consortium data. RESULT(S): The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, <1% Native Hawaiian/Other Pacific Islander, and 21% "Other". White males sought evaluation sooner (3.5 ± 4.7 vs. 3.8 ± 4.2 years), had older partners (33.3 ± 4.9 vs. 32.9 ± 5.2 years), and more had undergone vasectomy (8.4% vs. 2.9%) vs. all other races. Black males were older (38.0 ± 8.1 vs. 36.5 ± 7.4 years), sought fertility evaluation later (4.8 ± 5.1 vs. 3.6 ± 4.4 years), fewer had undergone vasectomy (3.3% vs. 5.9%), and fewer had partners who underwent intrauterine insemination (8.2% vs. 12.6%) compared with all other races. Asian/Indo-Canadian/Indo-American patients were younger (36.1 ± 7.2 vs. 36.7 ± 7.6 years), fewer had undergone vasectomy (1.2% vs. 6.9%), and more had partners who underwent intrauterine insemination (14.2% vs. 11.9%). Indian/Native males sought evaluation later (5.1 ± 6.8 vs. 3.6 ± 4.4 years) and more had undergone vasectomy (13.4% vs. 5.7%). CONCLUSION(S): Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.

Genetics of CFTR and male infertility.

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

Genetics of hypogonadotropic hypogonadism.

Male congenital hypogonadotropic hypogonadism (CHH) is a heterogenous group of genetic disorders that cause impairment in the production or action of gonadotropin releasing hormone (GnRH). These defects result in dysfunction of the hypothalamic-pituitary-gonadal hormone axis, leading to low testosterone levels and impaired fertility. Genetic testing techniques have expanded our knowledge of the underlying mechanisms contributing to CHH including over 30 genes to date implicated in the development of CHH. In some cases, non-reproductive signs or symptoms can give clues as to the putative genetic etiology, but many cases remain undiagnosed with less than 50% identified with a specific gene defect. This leads to many patients labelled as "idiopathic hypogonadotropic hypogonadism". Medical and family history as well as physical exam and laboratory features can aid in the identification of hypogonadotropic hypogonadism (HH) that is associated with specific medical syndromes or associated with other pituitary hormonal deficiencies. Genetic testing strategies are moving away from the classic practice of testing for only a few of the most commonly affected genes and instead utilizing next generation sequencing techniques that allow testing of numerous potential gene targets simultaneously. Treatment of CHH is dependent on the individual's desire to preserve fertility and commonly include human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) to stimulate testosterone production and spermatogenesis. In situations where fertility is not desired, testosterone replacement therapies are widely offered in order to maintain virilization and sexual function.

Reproductive endocrinologists are the gatekeepers for male infertility care in North America: results of a North American survey on the referral patterns and characteristics of men presenting to male infertility specialists for infertility investigations.

OBJECTIVE: To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium. DESIGN: Standardized male infertility questionnaire. SETTING: Male infertility centers. PATIENT(S): Men presenting for fertility evaluation. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Demographic, infertility history, and referral data. RESULT(S): The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by "other." Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use. CONCLUSION(S): This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use.

Prevalence and Management of Incidental Small Testicular Masses Discovered on Ultrasonographic Evaluation of Male Infertility.

PURPOSE: We report the safety of surveillance of small testicular masses incidentally discovered during evaluation of male infertility. MATERIALS AND METHODS: We retrospectively reviewed a prospectively collected database to identify patients with male infertility found to have incidental small testicular masses (hypoechoic lesions less than 10 mm) on scrotal ultrasound. The men were offered close surveillance with interval imaging and office followup. Patient and imaging characteristics were collected to compare the surveillance and surgical groups with additional comparisons between benign and malignant pathologies to elucidate predictors of underlying malignancy. RESULTS: Of 4,088 men in whom scrotal ultrasound was completed for male infertility evaluation 120 (2.9%) were found to have a subcentimeter testicular mass. Average followup was 1.30 years (range 0.1 to 16.9). A total of 18 men (15%) proceeded to extirpative surgery while 102 remained on surveillance at last followup. In those with at least 1 month of followup the mean lesion growth rate was -0.01 mm per year. Reasons for surgery included testicular exploration for infertility, mass growth, positive tumor markers, history of testis cancer, concerning imaging characteristics and patient choice. Six of the 18 men who underwent surgery were found to have malignancy, which was seminoma in all. All malignant lesions were greater than 5 mm on initial imaging and demonstrated vascularity, although size and vascularity were not significantly different from those of benign lesions on final pathology findings. No patients demonstrated advanced or recurrent disease. CONCLUSIONS: Small testicular masses are not uncommon, especially in the infertile male population. Most of these masses do not show significant growth during long-term evaluation and can be safely surveilled with close followup.

Salvage penile prosthetic surgery utilizing temporary malleable implants.

The inflatable penile prosthesis (IPP) is an effective erectile dysfunction (ED) treatment modality when oral and injectable therapies fail to achieve satisfactory results. Unfortunately, infection of the prosthetic remains a dreaded complication occurring in a small fraction of patients despite advances in device design and surgical techniques. With a prosthetic infection or erosion, classic management has included removal of all hardware with thorough irrigation of the infected spaces. To prevent corporal fibrosis and scarring that can make a subsequent implant challenging, an immediate salvage procedure with a three-piece prosthesis has been advocated when possible. However, there has been recent interest in using malleable devices during salvage procedures to serve as a temporary implant and further improve outcomes. Based on a literature review of immediate salvage procedures for infected penile prostheses, management with typical Mulcahy washout and IPP reimplant may be quite successful in appropriately selected patients. Based on one case series and a second multicenter trial of malleable salvage procedures, utilizing a malleable as a temporary implant is similarly, if not more, successful at eradicating prosthetic infection. The malleable implant not only serves as a temporary space-filling corporal implant to prevent fibrosis, but may also prove an adequate destination therapy for some given the lower than expected rate of delayed conversion to inflatable prosthesis. Future studies are needed to better characterize the role of malleable devices for penile prosthetic salvage and query patient satisfaction with the malleable device and repeated surgeries.

Urothelial melanosis of the bladder.

Urothelial melanosis is a rare finding characterized by abnormal pigmentation noted on cystoscopic evaluation and histologically defined by melanin deposition in the urothelium. Although generally considered benign, few cases of urothelial melanosis have been reported in the literature and the risk of recurrence or progression remains largely unknown. Four cases associated with urothelial cell carcinoma have been previously described. Here, we report a case of urothelial melanosis and review previously published cases in the literature.

Recent advances in understanding & managing male infertility.

Male infertility remains a struggle to definitively diagnose and treat with many men labelled as "idiopathic infertility" and eventually requiring assisted reproductive techniques.  Along those lines, research groups are continuing to explore current social and environmental factors, including the obesity epidemic, and their effects on male fertility potential.  Novel biomarkers of natural fertility status and azoospermia etiology have additionally seen recent attention with ACRV1 and TEX101/ECM1 assays either currently or soon to be commercially available.  Despite these advancements, however, medical treatment options have seen little progress.  Though surgical therapies have similarly seen little transformation, groups are exploring the use of testicular sperm for couples with elevated sperm DNA fragmentation and either planned or previously failed IVF/ICSI.  Concerted collaborative efforts will be needed as we move forward to better understand the challenges men face when struggling to conceive.

Influence of increasing body mass index on semen and reproductive hormonal parameters in a multi-institutional cohort of subfertile men.

OBJECTIVE: To determine whether obesity affects serum and seminal measures of male reproductive potential among a multi-institutional cohort. DESIGN: Retrospective multi-institutional cohort study. SETTING: Infertility clinics. PATIENT(S): All men referred for male infertility evaluation from 2002 to 2014 (n = 4,440). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Collected reproductive parameters included hormonal (gonadotropins, T, E2, PRL) and semen analysis (ejaculate volume, sperm concentration, motility, normal morphology) data. Body mass index (BMI) was calculated for all patients with comparisons to reproductive parameters using univariate and multiparametric models. RESULT(S): Based on World Health Organization definitions, 30.9% of the cohort was normal weight (BMI 18.5-24.9), 45.1% overweight (25-29.9), and 23.3% obese (>30). Neither FSH nor LH demonstrated significant correlations with BMI on multivariate analysis. Total T (r = -0.27) and the T:E2 ratio (r = -0.29) inversely varied with BMI, whereas E2 (r = 0.13) had a direct correlation. On univariate analyses, BMI had weak but significant negative correlations with ejaculate volume (r = -0.04), sperm concentration (r = -0.08), motility (r = -0.07), and morphology (r = -0.04). All parameters remained significant on multivariate modeling with the exception of sperm motility. Rates of azoospermia and oligospermia were also more prevalent among obese (12.7% and 31.7%, respectively) compared with normal weight men (9.8% and 24.5%). CONCLUSION(S): In one of the largest cohorts of male fertility and obesity, serum hormone and semen parameters demonstrated mild but significant relationships with BMI, possibly contributing to subfertility in this population.

Seminal biomarkers for the evaluation of male infertility.

For men struggling to conceive with their partners, diagnostic tools are limited and often consist of only a standard semen analysis. This baseline test serves as a crude estimation of male fertility, leaving patients and clinicians in need of additional diagnostic biomarkers. Seminal fluid contains the highest concentration of molecules from the male reproductive glands, therefore, this review focuses on current and novel seminal biomarkers in certain male infertility scenarios, including natural fertility, differentiating azoospermia etiologies, and predicting assisted reproductive technique success. Currently available tests include antisperm antibody assays, DNA fragmentation index, sperm fluorescence in situ hybridization, and other historical sperm functional tests. The poor diagnostic ability of current assays has led to continued efforts to find more predictive biomarkers. Emerging research in the fields of genomics, epigenetics, proteomics, transcriptomics, and metabolomics holds promise for the development of novel male infertility biomarkers. Seminal protein-based assays of TEX101, ECM1, and ACRV1 are already available or under final development for clinical use. Additional panels of DNA, RNA, proteins, or metabolites are being explored as we attempt to understand the pathophysiologic processes of male infertility. Future ventures will need to continue data integration and validation for the development of clinically useful infertility biomarkers to aid in male infertility diagnosis, treatment, and counseling.

Reduced Postvasectomy Semen Analysis Testing With the Implementation of Special Clearance Parameters.

OBJECTIVE: To determine the applicability of postvasectomy special clearance parameters (<100,000 nonmotile sperm/mL on semen analysis) suggested by the American Urological Association and to define the associated cost savings with avoidance of further testing. MATERIALS AND METHODS: We retrospectively reviewed the cohort of men undergoing vasectomy from December 2009 to August 2012 at a single institution. Patient demographics and postvasectomy semen analysis (PVSA) results were collected for clearance parameter comparisons. RESULTS: During the study period, 230 patients underwent vasectomy with a mean ± SD age of 36.4 ± 6.5 years. Among the cohort, 83.5% were married and 95.2% had one or more children. The initial PVSA was completed by 111 (48.3%) patients at a mean of 17.8 weeks (range 4-45) following vasectomy. Sperm was identified on initial PVSA in 40 patients (36.0%); 1 patient was found to have motile sperm. Of 39 patients, 38 (97.4%) with nonmotile sperm on PVSA could be cleared to cease other contraceptives based on the most recent clearance guidelines. For those completing an initial PVSA, postvasectomy clearance increased from 64.0% to 98.2% representing a potential cost savings of $2356 in repeat semen testing. CONCLUSION: Postvasectomy contraceptive clearance can be greatly increased when rare nonmotile sperm parameters are included although postvasectomy semen testing compliance remains poor.

Sports-related testicular injuries and the use of protective equipment among young male athletes.

OBJECTIVE: To survey young male athletes to determine the self-reported prevalence of sports-related testicular injuries and use of protective equipment among adolescents and young adults. METHODS: A self-administered questionnaire was distributed to male students at local high schools and colleges. Respondents were asked about personal and team member usage of athletic cups and history of testicular injuries. Returned surveys were analyzed for descriptive statistics and compared between high school and college respondents. RESULTS: Approximately 1700 surveys were distributed and 731 returned. The mean age of all respondents was 17.7 years. Across all sports, 18% of athletes experienced a testicular injury during sports and 36.4% observed injuries in team members, whereas only 12.9% of respondents reported wearing athletic cups. The prevalence of testicular injuries for lacrosse, wrestling, baseball, and football was 48.5%, 32.8%, 21%, and 17.8%, respectively. Of athletes reporting a prior injury, 20.1% reported that they wear a cup now. Rates of athletic cup usage were significantly less for college baseball, football, and all respondents compared with their high school counterparts. CONCLUSION: Previously reported rates of testicular injury with sports participation may underestimate the prevalence of these injuries among adolescent and young adult athletes among whom testicular protective equipment is infrequently used.

Solitary Candida albicans Infection Causing Fournier Gangrene and Review of Fungal Etiologies.

Polymicrobial bacterial infections are commonly found in cases of Fournier gangrene (FG), although fungal growth may occur occasionally. Solitary fungal organisms causing FG have rarely been reported. The authors describe a case of an elderly man with a history of diabetes who presented with a necrotizing scrotal and perineal soft tissue infection. He underwent emergent surgical debridement with findings of diffuse urethral stricture disease and urinary extravasation requiring suprapubic tube placement. Candida albicans was found to be the single causative organism on culture, and the patient recovered well following antifungal treatment. Fungal infections should be considered as rare causes of necrotizing fasciitis and antifungal treatment considered in at-risk immunodeficient individuals.

COX-2 inhibitors arrest prostate cancer cell cycle progression by down-regulation of kinetochore/centromere proteins.

BACKGROUND: Previous studies have shown that COX-2 inhibitors inhibit cancer cell proliferation. However, the molecular mechanism remains elusive. METHODS: Prostate cancer LNCaP, 22Rv1, and PC3 cells were cultured and treated with the COX-2 inhibitors celecoxib and CAY10404. Knockdown of COX-2 in LNCaP cells was carried out using lentiviral vector-loaded COX-2 shRNA. Cell cycle progression and cell proliferation were analyzed by flow cytometry, microscopy, cell counting, and the MTT assay. The antagonists of EP1, EP2, EP3, and EP4 were used to examine the effects of the PGE2 signaling. The effect of COX-2 inhibitors and COX-2 knockdown on expression of the kinetochore/centromere genes and proteins was determined by RT-PCR and immunoblotting. RESULTS: Treatment with the COX-2 inhibitors celecoxib and CAY10404 or knockdown of COX-2 significantly inhibited prostate cancer cell proliferation. Flow-cytometric analysis and immunofluorescent staining confirmed the cell cycle arrested at the G2/M phase. Biochemical analysis showed that inhibition of COX-2 or suppression of COX-2 expression induced a dramatic down-regulation of key proteins in the kinetochore/centromere assembly, such as ZWINT, Cdc20, Ndc80, CENP-A, Bub1, and Plk1. Furthermore, the EP1 receptor antagonist SC51322, but not the EP2, EP3, and EP4 receptor antagonists, produced similar effects to the COX-2 inhibitors on cell proliferation and down-regulation of kinetochore/centromere proteins, suggesting that the effect of the COX-2 inhibition is through inactivation of the EP1 receptor signaling. CONCLUSIONS: Our studies indicate that inhibition of COX-2 can arrest prostate cancer cell cycle progression through inactivation of the EP1 receptor signaling and down-regulation of kinetochore/centromere proteins.

Cystoscopic removal of intravesical synthetic mesh extrusion with the aid of Endoloop sutures and endoscopic scissors.

Synthetic mesh is commonly used in urogynecologic surgical procedures for correction of stress urinary incontinence and pelvic organ prolapse. Bladder mesh extrusion is a recognized complication and frequently requires extensive mesh resection. We present a case of intravesical polypropylene mesh extrusion following a combined mesh kit and midurethral sling placement. A novel transurethral approach, employing Endoloop sutures with endoscopic scissors, was used to resect the protruding mesh located in close proximity to a ureteral orifice. Medline was searched for other minimally invasive treatment strategies for bladder mesh extrusion. Various techniques for minimally invasive resection of extruded intravesical mesh have been described in the literature. Our strictly transurethral approach avoids the use of an energy source and eliminates the need for open or extensive surgery. Advantages of this new transurethral operative technique include decreased risk of injury associated with the use of an energy source within the bladder and avoidance of open surgical complications.

Reflux anuria after prophylactic ureteral catheter removal: a case description and review of the literature.

In an attempt to reduce iatrogenic ureteral injury, urologists are frequently called on for placement of prophylactic ureteral catheters in difficult pelvic surgeries. Reflux anuria, which may be more appropriately termed catheter-induced obstructive anuria, has been reported as a complication of ureteral catheter placement and is characterized by the absence of urine output after ureteral manipulation because of edema and obstruction. We report a case of obstructive anuria after bilateral ureteral catheter removal and review the literature regarding this rare complication. Medline was searched for all relevant case reports, case series, and trials that included prophylactic ureteral catheters and described complications of their use. Published series report varying incidence of obstructive anuria after prophylactic ureteral catheter removal from 0% to 7.6%. There are no proven strategies for prevention of obstructive anuria after prophylactic ureteral catheter removal, but staged removal has shown a trend toward reduced incidence. When encountered, most cases of anuria after catheter removal resolved with medical management alone; however, indwelling stent placement has been advocated while ureteral edema resolves.

High-throughput identification of IMCD proteins using LC-MS/MS.

The inner medullary collecting duct (IMCD) is an important site of vasopressin-regulated water and urea transport. Here we have used protein mass spectrometry to investigate the proteome of the IMCD cell and how it is altered in response to long-term vasopressin administration in rats. IMCDs were isolated from inner medullas of rats, and IMCD proteins were identified by liquid chromatography/tandem mass spectrometry (LC-MS/MS). We present a WWW-based "IMCD Proteome Database" containing all IMCD proteins identified in this study (n = 704) and prior MS-based identification studies (n = 301). We used the isotope-coded affinity tag (ICAT) technique to identify IMCD proteins that change in abundance in response to vasopressin. Vasopressin analog (dDAVP) or vehicle was infused subcutaneously in Brattleboro rats for 3 days, and IMCDs were isolated for proteomic analysis. dDAVP and control samples were labeled with different cleavable ICAT reagents (mass difference 9 amu) and mixed. This was followed by one-dimensional SDS-PAGE separation, in-gel trypsin digestion, biotin-avidin affinity purification, and LC-MS/MS identification and quantification. Responses to vasopressin for a total of 165 proteins were quantified. Quantification, based on semiquantitative immunoblotting of 16 proteins for which antibodies were available, showed a high degree of correlation with ICAT results. In addition to aquaporin-2 and gamma-epithelial Na channel (gamma-ENaC), five of the immunoblotted proteins were substantially altered in abundance in response to dDAVP, viz., syntaxin-7, Rap1, GAPDH, heat shock protein (HSP)70, and cathepsin D. A 28-protein vasopressin signaling network was constructed using literature-based network analysis software focusing on the newly identified proteins, providing several new hypotheses for future studies.