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Summary Ganciclovir (GCV) inhibits spermatogenesis in preclinical studies but long‐term effects on fertility in renal transplant patients are unknown. In a prospective, multicenter, open‐label, nonrandomized study, male patients were assigned to Cohort A [valganciclovir (VGCV), a prodrug of GCV] (n = 38) or B (no VGCV) (n = 21) by cytomegalovirus prophylaxis requirement. Changes in semen parameters and DNA fragmentation were assessed via a mixed‐effects linear regression model accounting for baseline differences. Sperm concentration increased post‐transplant, but between baseline and treatment end (mean 164 days Cohort A, 211 days Cohort B), the model‐based change was lower in Cohort A (difference: 43.82 × 106/ml; P = 0.0038). Post‐treatment, sperm concentration increased in Cohort A so that by end of follow‐up (6 months post‐treatment) changes were comparable between cohorts (difference: 2.09 × 106/ml; P = 0.92). Most patients’ sperm concentration improved by end of follow‐up; none with normal baseline concentrations (≥20 × 106/ml) were abnormal at end of follow‐up. Changes in seminal volume, sperm motility/morphology, DNA fragmentation, and hormone levels were comparable between cohorts at end of follow‐up. Improvement in semen parameters after renal transplant was delayed in men receiving VCGV, but 6 months post‐treatment parameters were comparable between cohorts.

To determine if race/ethnicity impacts disclosure of erectile function.Data on age, education, erectile function, and past medical history were obtained from the National Health and Nutrition Examination Survey. Response rates to a single survey question regarding erectile function were calculated and compared between race/ethnicity groups. Two subgroups were created by excluding non-responders to questions about hypertension and prostate disease to control for overall non-responsiveness and urologic health literacy.Our final cohort consisted of 4,694 men. Overall, 3,898 (83.0%) responded to the erectile function survey question. Race/ethnicity was a significant factor in overall response rates to the Erectile function question: 85.2% in non-hispanic white, 82.3% in non-hispanic black, 81.2% in hispanic, and 64.8% in other subjects (P.001). Race/ethnicity remained significantly associated with responses rates among both subgroups. Multivariate logistic regression using the prostate disease subgroup showed that non-hispanic black (AOR = 2.02, 95% CI 1.01-4.03, P = .047) and hispanic (AOR = 2.18, 95% CI 1.19-4.00, P = .012) participants were significantly more likely to not disclose their erectile function compared to non-hispanic white participants after controlling for age and education.Non-hispanic black and hispanic men were significantly less likely to disclose their erectile function than non-hispanic white men in an anonymous, nationally representative survey. A better understanding of how cultural differences affect reporting of erectile function is important in improving patient care and accurately studying outcomes of urological procedures.

Men who ejaculate before or shortly after penetration, without a sense of control, and who experience distress related to this condition may be diagnosed with premature ejaculation (PE), while men who experience difficulty achieving sexual climax may be diagnosed with delayed ejaculation (DE). The experience of many clinicians suggest that these problems are not rare and can be a source of considerable embarrassment and dissatisfaction for patients. The role of the clinician in managing PE and DE is to conduct appropriate investigation, to provide education, and to offer available treatments that are rational and based on sound scientific data.The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. A research librarian conducted searches in Ovid MEDLINE (1946 to March 1, 2019), the Cochrane Central Register of Controlled Trials (through January 2019) and the Cochrane Database of Systematic Reviews (through March 1, 2019). An update search was conducted on September 5, 2019. Database searches resulted in 1,851 potentially relevant articles. After dual review of abstracts and titles, 223 systematic reviews and individual studies were selected for full-text dual review, and 8 systematic reviews and 59 individual studies were determined to meet inclusion criteria and were included in the review.Several psychological health, behavioral, and pharmacotherapy options exist for both PE and DE; however, none of these pharmacotherapy options have achieved approval from the United States Food and Drug Administration and their use in the treatment of PE and DE is considered off-label.Disturbances of the timing of ejaculation can pose a substantial impediment to sexual enjoyment for men and their partners. The Panel recommends shared decision-making as fundamental in the management of disorders of ejaculation; involvement of sexual partner(s) in decision making, when possible, may allow for optimization of outcomes.

Background Ejaculation consists of the emission of semen from seminal vesicles and prostate, followed by expulsion. Ejaculatory dysfunction may take several forms including premature ejaculation, delayed or anejaculation, retrograde ejaculation, and painful ejaculation. Ejaculation is what we can see whereas orgasm is what we feel. The presence of ejaculate does not indicate the ability to experience orgasm. Hence, for the purpose of this work we consider orgasm and ejaculation as 2 separate neurobiological phenomena. Aim To review the role of advanced investigative techniques such as perineal ultrasound in the diagnosis and management of ejaculation and ejaculatory dysfunction. Methods We performed a PubMed search for key words individually and in combination: “ejaculation,” “ejaculatory dysfunction,” “delayed ejaculation,” “painful ejaculation,” “retrograde ejaculation,” “perineal ultrasound,” and “transrectal ultrasound.” We also share our local experience using perineal ultrasound in assessing ejaculation. Outcomes Perineal ultrasound can be used as an aid in the investigation of ejaculatory dysfunction. Results Evaluation of ejaculatory function hinges on a detailed psychosexual history and appropriate physical examination. Function of the ejaculatory center in the spine is androgen dependent; thus, hormonal evaluation is an important aspect of the workup. Disorders of ejaculation and orgasm require evaluation of neuromuscular reflexes activated during sexual activity. Dynamic ultrasonographic (US) ejaculatory-orgasmic studies allow for reproducible and detailed descriptions of the sexual response. Transrectal ejaculatory studies are useful in uncovering reasons for lack of antegrade semen emission, especially in men with poor sperm production or after vasectomy. Dynamic US studies contribute clinical utility in its non-invasive nature and can provide insight to the dynamic processes surrounding pelvic floor functioning in men. Conclusions Perineal US for men with delayed ejaculation or anejaculation, painful ejaculation, or retrograde ejaculation may be helpful in select cases. Further research using this modality may help advance our understanding of ejaculatory dysfunction. Forbes CM, Flannigan R, Paduch DA. Perineal Ultrasound: a Review in the Context of Ejaculatory Dysfunction. Sex Med Rev 2018;6:419–428.

Objective To evaluate whether varicocelectomy improves both serum testosterone and sexual function, as assessed by the Male Sexual Health Questionnaire (MSHQ). Methods A retrospective chart review of patients who have undergone varicocelectomy and had both pre- and postoperative MSHQ was performed. The MSHQ is a clinically validated questionnaire that assesses erectile function, ejaculatory function, and sexual satisfaction, with higher scores indicating better function. Clinical parameters pre and postvaricocelectomy were compared with paired t test. Results Thirty-four patients met study criteria. Seventeen patients (50%) presented for infertility, and the remaining 13 had symptomatic varicocele associated with hypogonadism. Average postsurgical follow-up was 20.6 ± 12.5 months. The majority of men in the study had bilateral varicoceles and left grade III varicoceles. Significant improvements in the total MSHQ score (3.9 ± 8.7, P = .027), the MSHQ erectile function (1.2 ± 2.3, P = .007), and the MSHQ ejaculatory function (1.4 ± 3.1, P = .018) domains were seen. Fifteen (44%) men saw improvement in their erectile function and 18 (53%) saw improvement in ejaculatory function. The improvement in serum testosterone was also significant (136.0 ± 201.3 ng/dL, P = .007). Conclusion Microsurgical repair of varicocele not only improves testosterone, but also improves patient-reported erectile and ejaculatory functions. Patients can confidently be counseled that varicocelectomy has the potential to improve sexual function along with serum testosterone.

Study question Do human Sertoli cells in testes that exhibit the Sertoli cell-only (SCO) phenotype produce substantially less glial cell line-derived neurotrophic factor (GDNF) than Sertoli cells in normal testes? Summary answer In human SCO testes, both the amounts of GDNF mRNA per testis and the concentration of GDNF protein per Sertoli cell are markedly reduced as compared to normal testes. What is known already In vivo, GDNF is required to sustain the numbers and function of mouse spermatogonial stem cells (SSCs) and their immediate progeny, transit-amplifying progenitor spermatogonia. GDNF is expressed in the human testis, and the ligand-binding domain of the GDNF receptor, GFRA1, has been detected on human SSCs. The numbers and/or function of these stem cells are markedly reduced in some infertile men, resulting in the SCO histological phenotype. Study design, size, and duration We determined the numbers of human spermatogonia per mm2 of seminiferous tubule surface that express GFRA1 and/or UCHL1, another marker of human SSCs. We measured GFRA1 mRNA expression in order to document the reduced numbers and/or function of SSCs in SCO testes. We quantified GDNF mRNA in testes of humans and mice, a species with GDNF-dependent SSCs. We also compared GDNF mRNA expression in human testes with normal spermatogenesis to that in testes exhibiting the SCO phenotype. As controls, we also measured transcripts encoding two other Sertoli cell products, kit ligand (KITL) and clusterin (CLU). Finally, we compared the amounts of GDNF per Sertoli cell in normal and SCO testes. Participants/materials setting methods Normal human testes were obtained from beating heart organ donors. Biopsies of testes from men who were infertile due to maturation arrest or the SCO phenotype were obtained as part of standard care during micro-testicular surgical sperm extraction. Cells expressing GFRA1, UCHL1 or both on whole mounts of normal human seminiferous tubules were identified by immunohistochemistry and confocal microscopy and their numbers were determined by image analysis. Human GDNF mRNA and GFRA1 mRNA were quantified by use of digital PCR and Taqman primers. Transcripts encoding mouse GDNF and human KITL, CLU and 18 S rRNA, used for normalization of data, were quantified by use of real-time PCR and Taqman primers. Finally, we used two independent methods, flow cytometric analysis of single cells and ELISA assays of homogenates of whole testis biopsies, to compare amounts of GDNF per Sertoli cell in normal and SCO testes. Main results and the role of chance Normal human testes contain a large population of SSCs that express GFRA1, the ligand-binding domain of the GDNF receptor. In human SCO testes, GFRA1 mRNA was detected but at markedly reduced levels. Expression of GDNF mRNA and the amount of GDNF protein per Sertoli cell were also significantly reduced in SCO testes. These results were observed in multiple, independent samples, and the reduced amount of GDNF in Sertoli cells of SCO testes was demonstrated using two different analytical approaches. Large scale data N/A. Limitations, reasons for caution There currently are no approved protocols for the in vivo manipulation of human testis GDNF concentrations. Thus, while our data suggest that insufficient GDNF may be the proximal cause of some cases of human male infertility, our results are correlative in nature. Wider implications of the findings We propose that insufficient GDNF expression may contribute to the infertility of some men with an SCO testicular phenotype. If their testes contain some SSCs, an approach that increases their testicular GDNF concentrations might expand stem cell numbers and possibly sperm production. Study funding/competing interest(s) This research was funded by the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Centers for Translational Research in Reproduction and Infertility Program (NCTRI) Grant 1R01HD074542-04, as well as grants R01 HD076412-02 and P01 HD075795-02 and the U.S.-Israel Binational Science Foundation. Support for this research was also provided by NIH P50 HD076210, the Robert Dow Foundation, the Frederick & Theresa Dow Wallace Fund of the New York Community Trust and the Brady Urological Foundation. There are no competing interests.

To assess the efficacy of time-resolved MR angiography (MRA) in evaluating penile vasculature in patients with clinically suspected vascular anomalies contributing to their erectile dysfunction correlating with penile doppler ultrasound (PDUS) findings and clinical outcomes after surgical intervention. Men (n = 26) with signs of early vascular shunting on PDUS underwent time-resolved, contrast-enhanced (0.1 mMol/kg gadobutrol at 1 ml/s followed by saline flush) 3-dimensional spoiled gradient echo T1-weighted MRA sequence performed over 3 min with 4.6 s frame rate after intracavernosal injection of an erectogenic agent. Additional T1- and T2-weighted sequences were performed for anatomic co-localization and tissue characterization. MRA images were evaluated for early filling of draining veins as well as arteriovenous malformations and fistulas and correlated with findings at surgery. 29 MRA examinations on 26 patients (mean age 39 years) demonstrated abnormal early venous drainage (n = 22) as well as diminutive/delayed cavernosal enhancement (n = 3), incomplete tumescence (n = 2), and combined arterial inflow/venous outflow disease (n = 1). The MRA had a concordance of 85.2% at determining the presence, or lack thereof of a shunt/AVM when compared to PDUS. Time-resolved MRA allows for both temporal and spatial resolution with visualization of both arterial and venous abnormalities which may be suggested with a screening PDUS examination. This technique allows us to provide detailed anatomic information prior to any surgical intervention.

Background Mechanisms underlying delayed orgasm (DO) are poorly understood; however, known effects of psychotropic medications on sexual function provides a rationale for aberrant central nervous system signaling as a cause. Aim To compare brain activation between men with normal orgasm and those with lifelong DO during sexual stimulation using brain fMRI algorithms. Methods 3 subjects with self-reported life-long DO and 6 normal controls were included in this study. The International Index of Erectile Function, Male Sexual Health Questionnaire, and self-reported time to orgasm were used to assess sexual function. Subjects underwent a 3-T fMRI study while viewing 3 video clips: a neutral control (NC), a positive emotional control (EC), and a sexual condition (SC). Each video sequence was repeated 5 times, with 50-second clips presented in a randomized fashion. fMRI data were analyzed in a block design manner to determine areas of differential brain activation between groups. The Allen Brain Atlas of gene expression in the human brain was used to identify signaling pathways in the areas of differential fMRI activation between the DO and control groups. Outcomes The primary outcome was differential activation of fMRI neural activation between groups. Results Analysis of differential activation in the SC compared with the NC and EC revealed increased activation in the right frontal operculum (P = .003), right prefrontal gyrus (P = .003), and inferior occipital gyrus (P = .003). Increased activation in the right fusiform gyrus of the occipital lobe and the right hippocampus (P = .0004) was seen in the DO group compared with controls. Using the Allen Atlas of Human Brain Expression, we identified corresponding neurotransmitter receptors to this region, including adenosine receptors, muscarinic and nicotinic cholinergic receptors, cannabinoid receptors, and dopamine receptors, among others. Clinical Implications Lifelong DO in men may be due to abnormal neurotransmitter signaling leading to poor progression of arousal due to aberrant processing of sexual cues. Identification of neurotransmitter pathways by fMRI will aid the development of pharmacotherapeutic agents. Strengths & Limitations Strengths of this study include the novel application of functional neuroimaging to investigate the pathogenesis of DO. Limitations include the small sample size, making this study exploratory in nature. Conclusion This study revealed differences in brain activation on visualization of sexual stimuli in men with a history of DO compared with controls. Identified regions are rich in numerous neurotransmitter receptor subtypes and may be amenable to pharmacologic targeting to identify novel therapies for these men.

Introduction Ejaculatory dysfunctions other than premature ejaculation are commonly encountered in specialized clinics; however, their characterization in community-dwelling men is lacking. Aim The aim of this study was to evaluate the prevalence, severity, and associated distress of four ejaculatory dysfunctions: delayed ejaculation (DE), anejaculation (AE), perceived ejaculate volume reduction (PEVR) and/or decreased force of ejaculation (DFE) as a function of demographic and clinical characteristics in men. Methods Observational analysis of 988 subjects presenting with one or more types of ejaculatory dysfunctions other than premature ejaculation who screened for a randomized clinical trial assessing the efficacy of testosterone replacement on ejaculatory dysfunction. Demographic and clinical characteristics were assessed as potential risk factors using regression analysis. Main Outcome Measures The main outcome measures used were ejaculatory dysfunction prevalence and scores (3-item Men’s Sexual Health Questionnaire Ejaculatory Dysfunction-Short Form [MSHQ-EjD-SF]), and bother (MSHQ-EjD-SF Bother item) and sexual satisfaction/enjoyment (International Index of Erectile Function Questionnaire Q7, Q8) as a function of subject’s age, race, body mass index (BMI) and serum testosterone levels (measured by liquid chromatography tandem mass spectrometry). Results Mean (standard deviation [SD]) age of the participants was 52 years (11). Eighty-eight percent of the men experienced more than one type of ejaculatory dysfunction and 68% considered their symptoms to be bothersome. Prevalence of the ejaculatory dysfunctions was substantial across a range of age, race, BMI, and serum testosterone categories. Prevalence of PEVR and DFE were positively associated with age ( Conclusion The majority of the participants experienced multiple ejaculatory dysfunctions and found them to be highly bothersome. Ejaculatory dysfunctions were prevalent across a wide range of demographic and clinical characteristics.

Objective To evaluate assisted reproductive technology (ART) outcomes using testicular sperm in oligospermic men who previously failed to achieve paternity using TUNEL-positive ejaculated sperm. Design Retrospective cohort. Setting Academic medical center. Patient(s) Twenty-four oligospermic men who failed one or more ART cycles using ejaculated sperm with TUNEL-positive proportion >7%, and subsequently underwent microsurgical testicular sperm extraction (TESE). Intervention(s) TESE followed by intracytoplasmic sperm injection (ICSI). Main Outcome Measure(s) TUNEL-positive level in ejaculated and testicular sperm; clinical pregnancy. Result(s) The mean TUNEL-positive level was 24.5% for ejaculated sperm, and 4.6% for testicular sperm. Clinical pregnancy was achieved in the first ART cycle with testicular sperm in 12 (50%) out of 24 couples. There was no statistically significant difference in maternal and paternal age, maternal gravity and parity, number of previous ART attempts, concentration or motility of retrieved sperm, number of oocytes retrieved, fertilization rate, or number of embryos transferred between couples who did and did not achieve pregnancy. No miscarriages occurred. All 12 pregnancies resulted in the delivery of healthy children. Conclusion(s) The percentage of TUNEL-positive cells is lower in testicular sperm for oligospermic men who have abnormal ejaculated sperm DNA fragmentation. The use of testicular sperm for ICSI was associated with a 50% pregnancy and live-birth rate for couples who had previously failed one or more IVF–ICSI cycles with ejaculated sperm. No other clinical predictors of successful pregnancies after the use of surgically retrieved sperm could be identified. In men with elevated TUNEL-positive ejaculated sperm and failed ART, TESE may be considered.

Introduction Klinefelter syndrome (KS) is the result of sex chromosome aneuploidy most often characterized as 47,XXY. The typical features of KS include tall stature, gynecomastia, small firm testicles, hypergonadotropic hypogonadism, and infertility. However, abnormalities in neurodevelopment, cognition, and social and behavioral functioning also can be present. The abnormalities in neurodevelopment are believed to be due in part to androgen deficiency during early development and puberty. Aim To discuss the role of androgens in normal adolescent development; discuss the cognitive, behavioral, and social functioning of children with KS; evaluate the evidence for early androgen therapy in men with KS; and discuss management strategies in the development of boys with KS. Methods A systematic review of early androgen therapy and KS was performed using PubMed-Medline and Scopus databases. Relevant articles commenting on social, behavioral, cognitive, and physical outcomes among infants, children, and adolescents were included for reporting and discussion. Main Outcome Measures Social and behavior functioning; cognitive outcomes; adverse effects associated with androgen therapy. Results 3 retrospective articles and 2 randomized controlled trials addressing early androgen therapy in boys with KS were reviewed. These studies showed an improvement in several aspects of social and cognitive functioning based on validated questionnaires. Treatment strategies, potential negative effects, and limitations of the literature on early androgen therapy in boys with KS are discussed. Conclusion Our findings indicate that early androgen supplementation in children with KS combined with specific educational, family, and social support improves behavioral functioning. The optimal timing of hormonal therapy might require prospective studies, but based on our data and review of the literature, the benefit of early hormonal and therapeutic intervention in KS is very encouraging. Flannigan R, Patel P, Paduch DA. Klinefelter Syndrome. The Effects of Early Androgen Therapy on Competence and Behavioral Phenotype. Sex Med Rev 2018;6:595–606.

The aim of this study was to design a molecular assay for the diagnosis of Klinefelter syndrome (KS), based on the detection of supernumerary X-chromosomes (X-chs). DNA was extracted from peripheral blood samples of twenty-six 47,XXY males; two 46,XY/47,XXY males; twenty-two 46,XY males; and 15 females; and deaminated. Methylation-specific quantitative polymerase chain reaction (MS-qPCR) was performed using primers for unmethylated and methylated copies of the X-ch inactive-specific transcript (XIST-U and XIST-M) gene. X-ch disomy was determined on the basis of XIST methylation status. Degree of mosaicism in the 46,XY/47,XXY males was compared with karyotype and fluorescent in situ hybridization (FISH) results. Data analysis was performed using the Roche® LightCycler software V. 3.5.3., including determination of crossing points (CPs) by fit-point analysis and melting curve analysis. X-ch disomy was detected in all female controls and KS patients; male controls expressed XIST-M only. CPs ranged from 29.5 to 32.5 (standard deviation (s.d.) 0.8) for XIST-U and from 29 to 31 (s.d. 0.6) for XIST-M. Limit of detection of mosaicism was 1%. Based on XIST-U/XIST-M ratios for the two 47,XXY/46,XY patients, the calculated degree of mosaicism (1.8% and 17.8%) was comparable to FISH results (2.3% and 15%, respectively). Turnaround time from DNA deamination to final data analysis was under 9 h. We conclude that MS-qPCR is a sensitive, specific and rapid test for the detection of X-ch disomy, with applicability for the screening and diagnosis of KS, even in the setting of low grade 47,XXY/46,XY mosaicism.

We investigated the safety and tolerability of testosterone replacement therapy in adolescents with Klinefelter syndrome.We reviewed the medical records of all consecutive adolescents with Klinefelter syndrome evaluated between 2007 and 2012. Patients receiving testosterone replacement and aromatase inhibitor therapy were identified. Data on demographics, physical characteristics, medical history and serum hormone concentrations were collected for each patient. We evaluated longitudinal changes in serum testosterone, luteinizing hormone and follicle-stimulating hormone as well as changes in body mass index after the initiation of testosterone replacement therapy.We identified 151 adolescents with Klinefelter syndrome. Mean age at presentation was 11.6 years. Testosterone replacement therapy and aromatase inhibitors were initiated in 110 and 75 patients, respectively, at an average age of 13 to 14 years. Topical testosterone replacement therapy was used in 95% of patients with good clinical efficacy and compliance based on serial serum testosterone values. After the initiation of testosterone replacement therapy average serum testosterone improved from 240 to 650 ng/ml. Serum luteinizing hormone and follicle-stimulating hormone increased with the progression of puberty from 2.6 to 16.6 and 7 to 42 mIU/ml, respectively. No adverse outcomes related to testosterone replacement therapy were reported.Hormone supplementation with testosterone and aromatase inhibitors in adolescents with Klinefelter syndrome appears to be safe and effective for maintaining serum testosterone within the normal range. Compliance with topical formulations is high. Topical testosterone replacement therapy is not associated with the suppression of endogenous serum luteinizing hormone or follicle-stimulating hormone.

Sperm chromatin damage has been associated with male infertility, increased risk for spontaneous abortion, and poor embryo development. Available methods for detecting chromatin damage render the sperm no longer suitable for clinical use. Early apoptotic events resulting in chromatin damage are associated with increased permeability of the cell membrane to large ions. We propose the use of a large fluorescent organic cation, proprietary fluorochrome (PF-1), for fluorescence-activated cell sorting (FACS) for negative selection of sperm without chromatin damage. Sperm with chromatin damage are PF-1 positive. Performance of cell sorting by PF-1 was verified with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) after FACS on PF-1(+) and PF-1(-) subpopulations. Whereas 19.5% of PF-1 positive sperm were TUNEL positive only 1.5% sperm in the PF-1(-) fraction were TUNEL positive (p 0.00001). TUNEL values below 1.9% were considered background fluorescence. Post-sorting motility and vitality were 49.4% (SD: 12.5) and 65.0% (SD: 14.99), respectively. Proprietary fluorochrome activated sperm sorting may decrease or most likely eliminate all of TUNEL positive sperm without adverse effects on viability, providing a new therapeutic avenue for men with a high percentage of TUNEL positive sperm. Further research is needed to determine if the reduction in TUNEL positive sperm using PF-1 will improve in vitro fertilization (IVF) outcomes.

47, XXY or Klinefelter syndrome (KS), the most common chromosomal aberration in males, is characterized by either absolute or relative hypogonadism with frequent decline in serum testosterone (T) following the onset of puberty. Decreased T levels are the result of testicular dysfunction with decrease in size of Leydig cells, and loss of germs and Sertoli cells leading to tubular hyalinization. Increase in estradiol results from over-expression of aromatase CYP19. Deficient androgen production and observed varied response of end-organs to T leads to delayed progression of puberty with decreased facial/body hair, poor muscle development, osteoporosis, and gynecomastia. It is possible that hypogonadism and excessive estradiol production contribute to emotional and social immaturity, and specific learning disabilities in KS. Based on the authors' experience and literature review, early fertility preservation and hormonal supplementation may normalize pubertal development, prevent metabolic sequelae of hypogonadism, and have a positive effect on academic and social development. No randomized clinical trials are available studying the effects of T supplementation on reproductive or cognitive issues in KS. Aggressive T supplementation (topical gel) and selective use of aromatase inhibitors may be considered at the onset of puberty with careful follow-up and titration to reach age-specific high-normal physiologic serum values. The decision to institute hormonal therapy should be part of a multidisciplinary approach including physical, speech, behavioral, and occupational therapy. © 2013 Wiley Periodicals, Inc.

Maturation arrest (MA) refers to failure of germ cell development leading to clinical nonobstructive azoospermia. Although the azoospermic factor (AZF) region of the human Y chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. We sought to identify single genes on the Y chromosome that may be implicated in the pathogenesis of nonobstructive azoospermia associated with MA in the American population. Genotype-phenotype analysis of 132 men with Y-chromosome microdeletions was performed. Protein-coding genes associated with MA were identified by visual analysis of a genotype-phenotype map. Genes associated with MA were selected as those genes within a segment of the Y chromosome that, when completely or partially deleted, were always associated with MA and absence of retrievable testicular sperm. Expression of each identified gene transcript was then measured with quantitative RT-PCR in testicular tissue from separate cohorts of patients with idiopathic MA and obstructive azoospermia. Ten candidate genes for association with MA were identified within an 8.4-Mb segment of the Y chromosome overlapping the AZFb region. CDY2 and HSFY were the only identified genes for which differences in expression were observed between the MA and obstructive azoospermia cohorts. Men with obstructive azoospermia had 12-fold higher relative expression of CDY2 transcript (1.33 ± 0.40 vs. 0.11 ± 0.04; P=0.0003) and 16-fold higher expression of HSFY transcript (0.78 ± 0.32 vs. 0.05 ± 0.02; P=0.0005) compared to men with MA. CDY2 and HSFY were also underexpressed in patients with Sertoli cell only syndrome. These data indicate that CDY2 and HSFY are located within a segment of the Y chromosome that is important for sperm maturation, and are underexpressed in testicular tissue derived from men with MA. These observations suggest that impairments in CDY2 or HSFY expression could be implicated in the pathogenesis of MA.

Klinefelter syndrome (KS) remains the most common, yet often undiagnosed, chromosomal aberration in men. Early diagnosis and treatment can improve the health of patients with KS. The aim of this study was to evaluate the inactivation pattern of supernumerary X chromosomes. The secondary aim was to design a reliable and cost-effective molecular test for detection of X chromosome disomy. Methylation-specific polymerase chain reaction (M-PCR), with primers for familial mental retardation (FMR1) and X chromosome inactive-specific transcript (XIST) genes, was used to detect the presence of X chromosome disomy in men. Seventeen fertile males, 12 females, and 35 males with KS (28 with 47,XXY karyotype, and 7 with 47,XXY/46,XY mosaics) were included in the study. Results of the karyotype were compared with the results of semiquantitative M-PCR. Inactivation of X chromosomes was measured by XIST/FMR-1 methylation ratio. Differences in the methylation patterns of FMR1 and XIST genes between 46,XY men and men with X chromosome disomy allowed for rapid detection of the presence of an additional X chromosome, achieving 100% sensitivity and specificity using M-PCR. The methylated:unmethylated FMR1 amplicon ratio allowed the detection of 1 additional X chromosome per 100 normal XY cells (1% of XX/XY mosaicism). In our series, 50% of 47,XXY men showed skewed inactivation of the X chromosome. Men with KS can have incomplete inactivation of supernumerary X chromosomes. M-PCR is a sensitive, specific, fast, and relatively inexpensive test for the diagnosis of X chromosome disomy.

The phenotypic effects of the gr/gr partial azoospermia factor c deletion vary geographically and to our knowledge have not been reported in the American population. We evaluated the clinical characteristics of infertile American men with the gr/gr deletion.We retrospectively reviewed clinical data on 1,410 infertile men tested for the gr/gr deletion. We analyzed sperm concentration and the outcome of microdissection testicular sperm extraction with respect to gr/gr status.We identified 73 men with gr/gr deletions, including 43 of 989 (4.3%) with azoospermia, 18 of 317 (5.7%) with severe oligospermia (less than 5 million sperm per ml), 6 of 61 (9.8%) with oligospermia (5 to less than 20 million sperm per ml) and 6 of 43 (14%) infertile men with normospermia (greater than 20 million sperm per ml). A gr/gr deletion correlated with higher sperm production. The gr/gr deletion rate was higher in men with normospermia than in those with a sperm concentration of less than 20 million and less than 5 million per ml (p = 0.021 and 0.006, respectively). Microdissection testicular sperm extraction was done in 22 azoospermic men with gr/gr deletions and sperm were retrieved in 14 (64%). This retrieval rate was similar to that at our center in men with idiopathic nonobstructive azoospermia (p = 0.13).Diagnosis of the gr/gr deletion did not predict impaired sperm production in our patient population and did not appear to alter the prognosis for surgical sperm retrieval. Despite the established modulatory impact of the gr/gr deletion on sperm production in some populations at this time the clinical value of testing infertile American men for the gr/gr deletion is not clear.

Evaluation of potential candidates for testosterone replacement therapy (TRT) includes a complete medical history, physical examination, and hormonal screening. The choice of testosterone assay is important in clinical decision making. TRT should, in theory, approximate natural endogenous production of the hormone. There is no apparent association between TRT and the development of prostate cancer. The administration of exogenous testosterone is not a means of reversing the aging process in men with normal testosterone levels, but it may offer considerable benefit for those with hypogonadism.

Purpose of review Recent findings in the physiology and neurobiology of ejaculation have expanded our understanding of male sexual function and have allowed the development of new instruments to investigate ejaculatory and orgasmic disorders. Recent findings The evidence-based definition of lifelong premature ejaculation has set a model in the evaluation and treatment outcome of sexual dysfunction. New instruments to objectively assess arousal, orgasm and the expulsion phase of ejaculation such as functional MRI, dynamic pelvic ultrasound, PET scans and validated questionnaires have lead to a better understanding of sexual dysfunction in men. Animal models, developments in neurobiology and clinical experience have transformed a purely psychoanalytical approach to ejaculatory and orgasmic function into a novel multidisciplinary, scientifically sound and evidence-based discipline of medicine. Summary Ejaculation is an integral part of normal sexual function. Ejaculatory dysfunction is common and may cause substantial disruption to the quality of a patient's life. A better understanding of the epidemiology, pathophysiology, neuroscience and genetics of ejaculatory and orgasmic function will eventually lead to the development of new, effective methods of treatment of disorders of ejaculation and orgasm in men.

Lower urinary tract infections (UTIs) are common among the general population and are most often caused by bacterial pathogens. Viruses are an uncommon cause of UTIs in an immunocompetent host; however, viruses are increasingly recognized as the cause of lower UTI, especially hemorrhagic cystitis, among immunocompromised patients. BK virus, adenovirus, and cytomegalovirus are predominant pathogens involved in hemorrhagic cystitis after stem cell and solid organ transplantation, and their early diagnosis and treatment may prevent significant morbidity of hemorrhagic cystitis. The diagnosis of viral lower UTI is based on molecular techniques, and real-time polymerase chain reaction is often the method of choice because it allows for quantification of viral load. Cidofovir is becoming a drug of choice in viral UTIs because it is active against the most common viral pathogens. This review discusses the epidemiology, pitfalls in diagnosis, and current treatment of viral UTIs.

Hypogonadism is defined as decreased testosterone levels in men. Hypogonadism can be accompanied by erectile, orgasmic, and ejaculatory dysfunction.To evaluate whether treatment with testosterone solution 2% (testosterone) could improve ejaculatory function in a cohort of hypogonadal men.Sexually active, hypogonadal men at least 18 years old (total testosterone300 ng/dL) were randomized to receive testosterone or placebo for 12 weeks.Effects of testosterone on primary outcomes were evaluated using the International Index of Erectile Function (IIEF) and the Men's Sexual Health Questionnaire, Ejaculatory Dysfunction, Short Form (MSHQ-EjD-SF) questionnaires. Treatment differences were calculated using analysis of covariance.In total, 715 men (mean age = 55 years) were randomized to placebo (n = 357) or testosterone (n = 358). Most sexually active men who reported IIEF scores had some degree of erectile dysfunction (IIEF erectile function score26). Although ejaculatory function score (MSHQ-EjD-SF) improved in the testosterone group compared with placebo (P.001), improvement on the "bother" item did not reach statistical significance. Treatment-related adverse events in the testosterone group affecting at least 1% of patients were increased hematocrit, upper respiratory tract infection, arthralgia, burning sensation, fatigue, increased prostate-specific antigen, erythema, and cough. Few patients in either treatment group developed at least one adverse event leading to discontinuation (testosterone = 1.98% vs placebo = 3.09%; P = .475).Hypogonadal men receiving testosterone solution 2% therapy experience significantly greater improvement in ejaculatory function, compared with placebo, as assessed by the MSHQ-EjD-SF. However, improvement in "bother" was not statistically different between the two groups. Testosterone therapy was generally well tolerated.

Low T levels have been associated with ejaculatory dysfunction (EjD) in cross-sectional studies; however, the efficacy of T replacement in improving EjD has not been studied in a randomized controlled trial.To evaluate the efficacy of T replacement in androgen-deficient men with EjD.A multicenter, double-blind, randomized, placebo-controlled, 16-week trial with T solution 2% versus placebo.Medical centers in the United States, Canada, and Mexico.Seventy-six men with one or more EjD symptoms, including delayed ejaculation, anejaculation, reduced ejaculate volume, and/or reduced force of ejaculation, and two total T levels300 ng/dL (10.41 nmol/L) measured with liquid chromatography tandem mass spectrometry.Sixty milligrams of T solution 2% or placebo applied to the axillae for 16 weeks.The primary outcome was a change in the score of the three-item Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form (MSHQ-EjD-SF); secondary outcomes included measured ejaculate volume, scores of the bother/satisfaction item of the MSHQ-EjD-SF, the orgasmic function domain of the International Index of Erectile Function Questionnaire, and the sexual activity log.Seventy-six participants were randomized; 66 completed the study. Baseline demographic and clinical characteristics were comparable between the treatment arms. T replacement improved the MSHQ-EjD-SF score (mean score change, +3.1); however, this effect was not statistically different from placebo (mean score change, +2.5; P = .596). No differences were seen in any of the secondary outcomes or frequency of adverse events.T replacement was not associated with significant improvement in EjD in androgen-deficient men.

Background The utilization of penile prosthesis (PP) insertion in the general population for medically refractory erectile dysfunction (ED) has not been well-characterized. This study assessed the national temporal trends in the surgical management of ED utilizing PP. Materials and Methods An analysis of the 5% Medicare Public Use Files from 2001 to 2010 was performed to assess the use of PP. Regression analysis was performed to identify factors associated with PP placement, type of PP utilized, and factors associated with revisions. Results A total of 1,763,260 men were diagnosed with ED, 3% (53,180) of whom underwent PP insertion. The utilization of PP for ED decreased from 4.6% in 2002 to 2.3% in 2010 (P 1 were more likely to have a PP inserted for ED (P Conclusions The surgical management of ED with PP changed significantly between 2001 and 2010. The overall utilization of PP decreased, but its use in patients with significant medical comorbidities increased. Age >65, ethnicity, and geography influenced the likelihood of PP placement, prosthesis type, as well as the likelihood of prosthesis removal or revision.

Testicular cancer and infertility affect a similar age group of patients and have common biologic, epidemiologic, and environmental backgrounds. In this review, we provide current literature on links between infertility and testicular cancer, and new developments in the management of testicular cancer aimed at improving quality of life in men with testicular cancer.In-utero environmental exposure to endocrine disruptors modulates the genetically determined fate of primitive gonad and results in testicular dysgenesis syndrome, which may result in infertility and testicular cancer. Excellent response of testicular cancer to radiation and chemotherapy results in over 90% of survival and quality of life--fertility and sexual function--is of significant concern to patients and clinicians. The testicular-sparing management of testicular masses emerges as a sound alternative to radical orchiectomy and allows for preservation of spermatogenesis and hormonal function, and at the same time achieving similar survival rates. Secondary malignancies, pulmonary, and cardiovascular complications are recognized as late complications of treatment for testicular cancer.Better understanding of common mechanisms involved in infertility and testicular cancer, and scientifically driven evidence-based treatment options should improve quality of life in young men faced with this potentially life-threatening disease.

The aim of this study was to investigate expression of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) in paratesticular tissues obtained from boys with undescended testes.A total of 65 boys with unilateral cryptorchidism and failed human chorionic gonadotropion treatment underwent orchiopexy. A small sample of gubernaculum, cremasteric muscle and processus vaginalis was obtained. A total of 57 boys who underwent inguinal hernia repair served as the control group. All boys in the control group had testes in the scrotum. The expression of estrogen receptor alpha and progesterone receptor was measured by counting the number of ERalpha or PR positive cells detected by immunohistochemical analysis.ERalpha and PR density was higher in cremasteric muscle and processus vaginalis obtained from boys with undescended testes than in the control group. Density of progesterone receptor in the examined groups was lower than the density of estrogen receptor.ERalpha and PR are expressed in paratesticular tissues important for normal testicular descent. ERalpha was over expressed in cremasteric muscle and processus vaginalis in boys with undescended testes previously treated with human chorionic gonadotropin.

A varicocele can be defined as an abnormal tortuosity and dilation of the veins of the pampiniform plexus. Idiopathic varicocele is usually asymptomatic. It is noticed as an asymmetry in scrotal size, and presents as heaviness in the scrotum, or rarely with testicular pain. In most cases the adolescent is unaware of the varicocele and it is discovered during a regular physical examination or during examination for military service. The incidence of high-grade varicocele is approximately 5 % throughout the world. Varicocele is associated with a time dependant growth arrest in adolescents and adult males. There is a clear association between varicocele, infertility and testicular growth arrest. It is also known that varicocelectomy can reverse testicular growth arrest in adolescents. These facts have raised the question of how to best manage the adolescents with a varicocele. Adolescents do not present with infertility and thus should prophylactic repair be performed to prevent infertility in the future? Who would benefit the most by varicocelectomy: the adolescents with testicular growth arrest or any adolescent with a varicocele? Is it better to wait for a semen analysis or offer earlier treatment based on testicular growth arrests? These questions can be only answered when we have better understanding of the pathophysiology of varicocele. The purpose of this review is to present the current literature on adolescent varicocele and provide guidelines to the clinician how to manage the adolescents with a varicocele.

To evaluate the relationship of testosterone-enhancing therapy on alkaline phosphatase (AP) in relation to bone mineral density (BMD) in hypogonadal men.Retrospective review of 140 men with testosterone levels of350 ng/dL undergoing testosterone-enhancing therapy and followed for 2 years. Follicle-stimulating hormone, luteinising hormone, free testosterone, total testosterone, sex hormone binding globulin, calcium, AP, vitamin D, parathyroid hormone, and dual-energy X-ray absorptiometry (DEXA) scans were analysed. A subgroup of 36 men with one DEXA scan before and one DEXA 2 years after initiating treatment was performed.Analysis of the relationship between testosterone and AP at initiation of therapy using stiff linear splines suggested that bone turnover occurs at total testosterone levels of250 ng/dL. In men with testosterone levels of250 ng/dL, there was a negative correlation between testosterone and AP (R(2) = -0.347, P0.001), and no correlation when testosterone levels were between 250 and 350 ng/dL. In the subgroup analysis, the mean (sd) testosterone level was 264 (103) ng/dL initially and 701 (245), 539 (292), and 338 (189) ng/dL at 6, 12, and 24 months, respectively. AP decreased from a mean (sd) of 87 (38) U/L to 57 (12) U/L (P = 0.015), 60 (17) U/L (P0.001), and 55 (10) U/L (P = 0.03) at 6, 12, and 24 months, respectively. The BMD increased by a mean (sd) of 20 (39)% (P = 0.003) on DEXA.In hypogonadal men, the decrease in AP is associated with an increase in BMD on DEXA testing. This result suggests the use of AP as a marker of response to therapy.

Diagnostic tests should detect disease, have prognostic value, and aid in clinical decision making. Nowhere else in laboratory medicine does one have to interpret a subject's results within the dynamic of a couple as in reproductive medicine. Abnormal markers of male reproduction do not necessarily mean sterility, but instead indicate problems with spermatogenesis, sperm maturation, transport through epididymis and ejaculatory duct, or abnormal ejaculatory function. Decades of research suggest that one test will never fit all scenarios and a battery of assays evaluating different aspects of male reproduction will likely have the best prognostic value. There is a strong need for standardization and harmonization of evolving assays to establish their clinical relevance. Next-generation genome sequencing and the discovery of small noncoding RNAs in sperm already are changing the field and permit further insight into the biology of male reproduction as well as offer new diagnostic tests.

Serum testosterone does not correlate with androgen tissue activity, and it is critical to optimize tools to evaluate such activity in males. Ultrasound measurement of bulbocavernosus muscle (BCM) was used to assess the relationship between the number of CAG repeats (CAGn) in the androgen receptor (AR) and the BCM size; the changes in the number of CAGn over age were also evaluated. Transperineal ultrasound measurement of the BCM was also performed. AR CAGn were determined by high performance liquid chromatography, and morning hormone levels were determined using immunoassays. Forty-eight men had CAG repeat analysis. Twenty-five were 45 years of age, mean 53 years (s.d. = 5.58). The median CAGn was 21 (13-29). BCM area was greater when the number of CAGn were 24 (P = 0.04). There was a linear correlation between the number of CAGn and the BCM area R 2 = 16% (P = 0.01). In the 45 to 65-years-old group, a much stronger negative correlation (R 2 = 29%, P = 0.01) was noticed. In the 19 to 29-years-old group, no such correlation was found (R 2 = 4%, P = 0.36). In older men, the number of CAGn increased with age (R 2 = 32%, P = 0.01). The number of CAGn in the AR correlates with the area of the BCM. Ultrasound assessment of the BCM is an effective surrogate to evaluate end-organ activity of androgens. The number of CAGn may increase with age.

Objective To assess effects of tadalafil vs placebo on prostatic blood flow measured by transrectal ultrasonography in men aged ≥45 years with moderate-to-severe benign prostatic hyperplasia-lower urinary tract symptoms. Methods After screening and washout, patients were randomized to placebo (n = 50) or tadalafil 5 mg (n = 47) once daily for 8 weeks. Transrectal ultrasonography was performed at baseline, 4, and 8 weeks. The primary efficacy measure was the prostate transition zone (TZ) resistive index (RI). Secondary efficacy measures were RI in the peripheral zone and bladder neck, color pixel intensity (CPI), and color pixel density (CPD) in all 3 regions. Outcomes were assessed using mixed-model repeated-measures analyses. Results The overall treatment effect (tadalafil vs placebo) for the change from baseline through week 8 in prostate TZ RI was not statistically significant (least squares mean change: placebo, −0.01; tadalafil, 0.00; P = .118), nor was the change from baseline in prostate TZ CPI (P = .564) or CPD (P = .592). Results were similar for all flow measures in prostate peripheral zone and bladder neck. The adverse event profile was consistent with previous studies with no new safety findings. Conclusion Tadalafil for 8 weeks in men with BPH-LUTS did not result in detectable decreases in arterial RI or increases in CPI or CPD in the prostate or bladder neck. Detection of changes may not be possible because of already low baseline RI, insufficient sensitivity of techniques used, or may have been confounded by methodologic variability across sites. Alternatively, other possible mechanisms not assessed in this study may be more prominently involved.

Purpose Estradiol (E2) modulates testicular functions including steroidogenesis, but the mechanisms of E2 signaling in human testis are poorly understood. GPER-1 (GPR30), a G protein-coupled membrane receptor, mediates rapid genomic and non-genomic response to estrogens. The aim of this study was to evaluate GPER-1 expression in the testis, and its role in estradiol dependent regulation of steroidogenesis in isolated rat Leydig cells and human testis. Materials and Methods Isolated Leydig cells (LC) from adult rats and human testicular tissue were used in this study. Expression and localization studies of GPER-1 were performed with qRT-PCR, immunofluorescence, immunohistochemistry and Western Blot. Luteinizing Hormone (LH) -stimulated, isolated LC were incubated with estradiol, G-1 (GPER-1-selective agonist), and estrogen receptor antagonist ICI 182,780. Testosterone production was measured with radioimmunoassay. LC viability after incubation with G-1 was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Results GPER-1 mRNA is abundantly expressed in rat LC and human testis. Co-localization experiments showed high expression levels of GPER-1 protein in LC. E2-dependent activation of GPER-1 lowers testosterone production in isolated rats LCs and in human testis, with statistically and clinically significant drops in testosterone production by 20–30% as compared to estradiol-naive LC. The exposure to G-1 does not affect viability of isolated LCs. Conclusions Our results indicate that activation of GPER-1 lowers testosterone levels in the rat and human testis. The expression of GPER-1 in human testis, which lack ERα, makes it an exciting target for developing new agents affecting testosterone production in men.

Varicocele is the most important male factor responsible for decreased fertility potential in married couples. From March through June 1994, 2,470 school boys aged 10-20 years were examined to establish the incidence of consecutive grades of varicocele and to develop a protocol for diagnosis and treatment of adolescents with varicocele. Grade 1 varicocele was found in 18%, grade 2 in 12%, and grade 3 in 5% of the population examined. An original protocol of ultrasonographic (US) examination (previously verified by angioscintigraphy) was introduced to assess boys with clinically diagnosed varicocele. The volume of each testis, testicular volume decrease (TVD), pampiniform vein diameter (PVD), and basal (BBF) and maximum blood flow (MBF) velocities were measured in 625 boys. In 74 cases a semen analysis was performed. The statistical analysis revealed that the presence of venous reflux and PVD correlated with the grade of varicocele. Decreases in testicular volume were highly dependent on the grade of varicocele, PVD, and BBF and MBF velocities. Analysis of the relationship between spermatic (boys over 17 years) and US findings revealed that the quality of spermatogenesis can be predicted by US examination in adolescents with varicocele. The authors recommend multiparametric US examination as a reliable, objective, and repeatable technique for establishing criteria for operative treatment in boys under 18 years of age with varicocele as well as for postoperative evaluation.

The evaluation and treatment of hypogonadal men has become an important part of urologic practice. Fatigue, loss of libido, and erectile dysfunction are commonly reported, but nonspecific symptoms and laboratory verification of low testosterone (T) are an important part of evaluation in addition to a detailed history and physical examination. Significant intraindividual fluctuations in serum T levels, biologic variation of T action on end organs, the wide range of T levels in human serum samples, and technical limitations of currently available assays have led to poor reliability of T measurements in the clinical laboratory setting. There is no universally accepted threshold of T concentration that distinguishes eugonadal from hypogonadal men; thus, laboratory results have to be interpreted in the appropriate clinical setting. This review focuses on clinical, biological, and technological challenges that affect serum T measurements to educate clinicians regarding technological advances and limitations of the currently available laboratory methods to diagnose hypogonadism. A collaborative effort led by the American Urological Association between practicing clinicians, patient advocacy groups, government regulatory agencies, industry, and professional societies is underway to provide optimized assay platforms and evidence-based normal assay ranges to guide clinical decision making. Until such standardization is commonplace in clinical laboratories, the decision to treat should be based on the presence of signs and symptoms in addition to serum T measurements. Rigid interpretation of T ranges should not dictate clinical decision making or define coverage of treatment by third party payers.

Objective To evaluate surgical sperm retrieval rates in adolescents with Klinefelter syndrome and testosterone replacement therapy (TRT). Design Case series. Setting Academic medical center. Patient(s) Ten patients with Klinefelter syndrome, aged 14–22 years, treated with testosterone replacement and aromatase inhibitor therapy for a period of 1–5 years before surgical sperm retrieval. Intervention(s) Microsurgical testis sperm extraction with cryopreservation of harvested tissue. Main Outcome Measure(s) Presence of spermatozoa within testis tissue. Result(s) Successful sperm retrieval in 7/10 patients (70%). Conclusion(s) Use of topical TRT did not appear to suppress spermatogenesis in adolescents with KS. It is uncertain whether sperm retrieval rates would be higher or lower without testosterone replacement in these young males. Sperm cryopreservation should be discussed in all KS adolescents who are either receiving or considering initiating TRT.

To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED). To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction.Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated. EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively. Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5. Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10.A total of 3581 randomized subjects were studied. Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata. In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P0.001). Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P0.001) with severe OD reported improvement. Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction. Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD.Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction. Proportions of subjects reporting improved ejaculatory or orgasmic function were ≈ twofold higher with tadalafil than with placebo. These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).

Obesity concerns more than 200 million people in the world, with an increasing prevalence in western countries. It is closely related to multiple medical conditions, such as diabetes and hypertension. It was recently shown that testosterone deficiency syndrome and erectile dysfunction (ED) are also linked to male obesity. In this group of patients, ED may be due to defects in corpus cavernosum relaxation, endocrine modifications and nerve signal alterations. Weight loss and increased physical activities can improve erectile function in 30% of obese patients. Additional medical treatments of ED enhance erectile function in more than 80% of patients. Self image improvement associated with appropriate erectile dysfunction medical treatment allow better sexual life and potentially increased motivation for weight loss.

Apoptosis has been implicated in sperm chromatin damage; it is unclear whether apoptosis occurs through cytoplasmic or mitochondrial pathways. Sperm has minimal volume of cytoplasm but prominent mitochondria. Propidium iodide (PI), annexin V (AV), DiIC1(5) and proprietary fluorochrome (PF-1) were used to investigate apoptosis activation in human sperm using multichannel flow cytometry. There was a time-dependent increase in staining of spermatozoa with both AV and PF-1 and decrease in mitochondrial staining with DiIC1(5). These results strongly suggest that the drop in mitochondrial potential precedes changes in membrane phospholipids, and thus suggest apoptotic activation through mitochondrial pathway in human spermatozoa.

Objective To investigate the impact of early hormone replacement therapy (HT) on sperm retrieval rates in patients with Klinefelter syndrome (KS). Design A systematic review of the relevant literature using the PubMed NLM database. Result(s) There are no randomized controlled trials evaluating the impact of HT on sperm retrieval or reproductive outcomes in men with KS. On average, surgical sperm retrieval rates in men with KS are around 51%, with a range of 28%–69%. Young patient age is the most consistent positive predictor of sperm retrieval. Lower retrieval rates have been reported in a small subset of KS adults who previously received exogenous T, although the nature, duration, and reason for such therapy in these patient subsets are unknown. Conclusion(s) Early HT is recommended in patients with KS, but its effect on fertility potential has not been definitively studied. Larger studies are needed to better answer this question. Cryopreservation of sperm-containing semen or testicular tissue from a significant proportion of affected adolescents is possible, even when containing very low numbers of spermatozoa, and should be considered to maximize future fertility potential.

Purpose of review To review physiology of prolactin (PRL), cause and managment of hyperprolactinemia, and discuss evolving diverse roles of PRL in men's health. Recent findings Hyperprolactinemia can be physiologically found after sexual activities, exercise, lactation, during pregnancy, and after stressful venipuncture. Elevated PRL can be caused by medications use, renal failure, hypothyroidism, and by prolactinoma - PRL secreting tumors. Symptomatic hyperprolactinemia and prolactinomas should be treated to lower PRL levels, decrease tumor size, and restore gonadal function. Three modes of treatment are typically utilized: pharmacological, radiosurgery with gamma radiation, and external beam radiation. Pharmacological treatment of prolactinomas is mainly based on dopamine agonists. The most frequently used dopamine agonists are bromocriptine and cabergoline. Cabergoline becoming the preferred drug in the treatment of prolactinomas because of higher response rate and less side-effects. Bromocriptine has been recently approved to improve glycemic control in diabetes mellitus. Summary PRL plays a diverse role in men's reproduction and health. Detecting and treating elevated PRL may not only improve infertility and hypogonadism but also have a positive effect on the metabolic profile of patient and control of glycemic control and metabolic profile - an important advantage considering dramatic and worldwide increase in obesity and diabetes.

To determine frequencies of, and risk factors for, ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) in men with different degrees of erectile dysfunction (ED).Baseline data from 28 ED trials were integrated and analysed. The International Index of Erectile Function Question 9 (IIEF-Q9; 'When you had sexual stimulation or intercourse, how often did you ejaculate?') and IIEF-Q10 ('How often did you have the feeling of orgasm with or without ejaculation?') were used to evaluate ejaculatory and orgasmic functions. Responses of 'almost never or never' or 'a few times (much less than half the time)' were taken as evidence of EjD or OD, respectively, whereas responses of 'almost always or always' or 'most times (much more than half the time)' were taken as evidence of normal function. Estimates of the relative risks (RRs) of EjD or OD were determined for multiple patient characteristics.Among 12,130 study participants with available data, only 5117 (42.2%) reported normal ejaculatory function, and 4321 (35.6%) normal orgasm, regardless of ED severity. Among subjects with poor ejaculatory function, 16.7% had mild ED, and among subjects with poor sensation of orgasm, 21.9% had mild ED. Frequencies of EjD and OD increased with increasing ED severity. Of the 5117 individuals with normal ejaculatory function, 796 (15.6%) had poor sensation of orgasm. Of the 4321 subjects with normal orgasm, 226 (5.2%) had poor ejaculatory function. Men with (vs without) EjD or OD tended to be younger: 53.7 vs 56.9 years and 54.2 vs 56.2 years, respectively. Factors associated with increased RRs of EjD and OD included cardiomyopathy (RR for EjD 1.74; RR for OD 1.59); cardiac failure (RR 1.40; 1.22); and baseline use (or history of use) of antipsychotics (RR 1.45; 1.30), selective serotonin reuptake inhibitors (RR 1.31; 1.27), and tricyclic antidepressants (RR 1.34; 1.28).EjD and OD occurred at baseline in more than one in three men enrolled in tadalafil trials. Even men with mild ED reported EjD or OD. Further studies are warranted to better understand the impacts of EjD and OD on male sexuality and quality of life.

• To investigate orgasmic outcomes in patients undergoing robotic-assisted laparoscopic radical prostatectomy (RALP) and the effects of age and nerve sparing on these outcomes.• Between January 2005 and June 2007, 708 patients underwent RALP at our institution. • We analysed postoperative potency and orgasmic outcomes in the 408 men, of the 708, who were potent, able to achieve orgasm preoperatively and available for follow-up.• Of men aged ≤60 years, 88.4% (198/224) were able to achieve orgasm postoperatively in comparison to 82.6% (152/184) of older men (P0.001). • Of patients who received bilateral nerve sparing (BNS) during surgery, 273/301 (90.7%) were able to achieve orgasm postoperatively compared with 46/56 (82.1%) patients who received unilateral nerve sparing and 31/51 (60.8%) men who received non-nerve-sparing surgery (P0.001). • In men ≤60 years who also underwent BNS, decreased sensation of orgasm was present in 3.2% of men, and postoperative orgasmic rates were significantly better than men ≤60 years who underwent unilateral or no nerve sparing (92.9% vs 83.3% vs 65.4%, respectively; P0.001). • Potency rates were also significantly higher in men ≤60 years and in those who underwent BNS.• Age and nerve sparing influence recovery of orgasm and erectile function after RALP. • Men ≤60 years old and those who undergo BNS are most likely to maintain normal sexual function.

Objective To evaluate heat shock factor Y chromosome (HSFY) mRNA as a biomarker for the presence of retrievable testicular sperm. Design Case-control study. Setting Academic medical center. Patient(s) Men with nonobstructive azoospermia (NOA). Intervention(s) Testicular tissue from men with successful or failed testicular sperm extraction was evaluated with qunatitative real-time polymerase chain reaction (qRT-PCR) for expression of HSFY mRNA. Main Outcome Measure(s) Area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and probability of sperm retrieval based on HSFY testing. Result(s) We found higher HSFY mRNA expression in testicular tissue from NOA patients in whom sperm were successfully retrieved compared with those in whom sperm were not found, with good discrimination between the groups in all histologic variants of NOA (AUC 0.89 overall, 0.98 for patients with Sertoli cell only [SCO] histology, 0.90 for patients with maturation arrest [MA] histology). Sensitivity and specificity were, respectively, 67% and 93% overall, 92% and 100% for SCO patients, and 67% and 92% for MA patients. The probabilities of sperm retrieval for HSFY-positive and -negative patients were, respectively, 93% and 31% overall, 100% and 7% for SCO patients, and 91% and 32% for MA patients. Conclusion(s) Detection of HSFY mRNA expression by qRT-PCR has promising application in the evaluation and counseling of men with NOA before attempted sperm retrieval surgery.

During their lifetime, 20% of men will suffer from a fracture secondary to osteoporosis, and morbidity and mortality of a hip fracture in men are more severe than in women. Despite these facts, there are only few studies on osteoporosis in men. Hyopgonadism is a known risk factor for bone mineral density decrease. Hypogonadism can be found in patients diagnosed with prostate cancer who are receiving androgen deprivation therapy, but can also be discovered in patients with male infertility or erectile dysfunction. Urologists have central role in men's health aftercare, and therefore have key role in the screening and in the multidisciplinary treatment of osteoporosis and osteopenia.

We report on a microfabricated silicon microprobe integrated with an ultrasonic actuator and polysilicon strain gauges for Microdissection Testicular Sperm Extraction (TESE) surgery. Multiple microprobe insertion experiments were performed on rat testis tissue and, by monitoring the tubule puncture artifacts in the force signal sensed by the microprobe, we were able to estimate the average diameter of the sperm-carrying tubules in the sample. We have demonstrated the ability to sense the existence of larger tubules embedded in a mass of thinner tubules, by means of an Area-Ratio based metric using an analytically calculated expression for the distribution of sizes measured by the microprobe. This information is important in microdissection TESE to distinguish tubules with and without fertile sperm, potentially eliminating the large incision currently required for optical spermatazoa localization.

Objective To evaluate the benefit of Y microdeletion testing. Design Retrospective analysis. Setting University-based male fertility clinic and genetics laboratory. Patient(s) A total of 1,591 men with sperm concentrations less than 5 million sperm/mL. Intervention(s) Semen analysis, Y microdeletion testing, microdissection testicular sperm extraction (TESE). Main Outcome Measure(s) Sperm concentration, incidence and nature of Y microdeletions, microdissection TESE outcome. Result(s) We identified 149 microdeletions (9.4%). 10.4% of azoospermic men and 10.1% of men with sperm concentrations >0–1 million sperm/mL harbored microdeletions. Two-thirds of microdeletions in azoospermic men were AZFa, AZFb, AZFb+c, or complete Yq deletions. Virtually all microdeletions in oligozoospermic patients were AZFc deletions. Seven hundred eighteen patients underwent microdissection TESE, including 41 with microdeletions. Microdissection TESE failed in all patients with AZFa, AZFb, AZFb+c, and complete Yq deletions. Sperm were retrieved in 15/21 AZFc deleted patients (71.4%). The presence of an AZFc deletion was associated with increased likelihood of sperm retrieval when compared with the 48.8% retrieval rate in 385 idiopathically azoospermic men who consecutively underwent microdissection TESE at our institution during the study period. Clinical pregnancy was achieved in 10/15 azoospermic AZFc deleted patients for whom sperm were successfully retrieved. Conclusion(s) Of azoospermic and severely oligozoospermic American men, 10% harbor Y microdeletions that alter prognosis for surgical sperm retrieval and are vertically transmissible. Y microdeletion testing is essential for genetic and preoperative counseling in these patients.

Klinefelter syndrome (KS) is the most common chromosomal aberration in men. There are approximately 250,000 men with KS in the United States, and the prevalence of KS in male reproductive practices is 3 to 4%; however, most men are never diagnosed. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state of the art care to children and men with KS. Over the last 10 years, with advancements in artificial reproductive techniques and the successful delivery of healthy children from men with KS, the involvement of reproductive endocrinologists and urologists in the care of patients with KS is becoming commonplace. The new areas of intense research investigate optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS. This review provides the latest update in our understanding of the pathophysiology, natural history, and evolving paradigms of therapy in adolescents and men with KS.

Objective To assess the effects of a selective serotonin reuptake inhibitor on semen parameters. Design Prospective study. Setting Academic medical center. Patient(s) Thirty-five healthy male volunteers, 18–65 years old. Intervention(s) Paroxetine administration for 5 weeks. Main Outcome Measure(s) Serum hormone levels, semen analyses, percent sperm DNA fragmentation, and questionnaire assessment of sexual function assessed before, during, and 1 month after drug administration. Result(s) Mean sperm DNA fragmentation was significantly higher for men while on paroxetine (30.3%) versus baseline (13.8%). Before paroxetine, 9.7% of patients had a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) score ≥30% compared with 50% at week 4 of treatment. The odds ratio (OR) of having abnormal DNA fragmentation while taking paroxetine was 9.33 (95% confidence interval, 2.3–37.9]. Multivariate logistic regression correcting for age and body mass index confirmed this correlation (OR, 11.12). Up to 35% of men noted significant changes in erectile function and up to 47% of men reported ejaculatory difficulties on medication. Recovery to near-normal sexual function was noted after stopping treatment. Standard semen parameters were not significantly altered during paroxetine treatment. Conclusion(s) In men with normal semen parameters, paroxetine induced abnormal sperm DNA fragmentation in a significant proportion of subjects, without a measurable effect on semen parameters. The fertility potential of a substantial number of men on paroxetine may be adversely affected by these changes in sperm DNA integrity.

Klinefelter syndrome, 47,XXY and its variants, is the most common chromosomal aberration among men, with estimated frequency of 1: 500 among newborns. Men with Klinefelter syndrome present with sequels of hormonal and spermatogenic testicular failure like infertility, low testosterone, erectile dysfunction, and low bone mineral density. This review is aimed to provide the practicing urologist with an important source of clinically relevant information about Klinefelter syndrome.Sperm can be found in over 50% of men with Klinefelter syndrome, thus men with Klinefelter syndrome are not sterile. Recent evidence suggests that children with Klinefelter syndrome are born with spermatogonia and lose large numbers of germ cells during puberty. Early diagnosis and treatment can improve the quality of life and the overall health of men with Klinefelter syndrome.Growing interest in Klinefelter syndrome among translational scientists and clinicians will result in better understanding of the pathophysiology of testicular failure. In some states, screening programs for Klinefelter syndrome are already in place, which will increase the number of patients with Klinefelter syndrome seen by practicing urologists in the near future. Diagnosis and management of patients with Klinefelter syndrome is within the scope and training of urologists. Development of randomized clinical trials comparing different forms of interventions in men and children with Klinefelter syndrome will allow us to standardize the care of these patients.