The epididymal immune balance: a key to preserving male fertility Allison Voisin, Fabrice Saez, Joël R Drevet, Rachel Guiton Asian Journal of Andrology 2019 21(6):531-539 Up to 15% of male infertility has an immunological origin, either due to repetitive infections or to autoimmune responses mainly affecting the epididymis, prostate, and testis. Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract. As a consequence, the epididymis, in which posttesticular spermatozoa mature and are stored, has raised some interest in recent years when it comes to its immune mechanisms. Indeed, sperm cells are produced at puberty, long after the establishment of self-tolerance, and they possess unique surface proteins that cannot be recognized as self. These are potential targets of the immune system, with the risk of inducing autoantibodies and consequently male infertility. Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells. These processes rely on incompletely described molecules and cell types. This review compiles recent studies focusing on the immune cell types populating the epididymis, and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response, while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.

Do I need to see a urologist for my vasectomy? A comparison of practice patterns between urologists and family medicine physicians Natasza M Posielski, Daniel D Shapiro, Xing Wang, Brian V Le Asian Journal of Andrology 2019 21(6):540-543 Urologists perform the majority of vasectomies in the United States; however, family medicine physicians (FMPs) perform up to 35%. We hypothesized that differences exist in practice patterns and outcomes between urologists and FMPs. Patients who underwent a vasectomy from 2010 to 2016 were identified. Postvasectomy semen analysis (PVSA) practices were compared between urologists and FMPs, before and after release of the 2012 AUA vasectomy guidelines. From 2010 to 2016, FMPs performed 1435 (35.1%) of all vasectomies. PVSA follow-up rates were similar between the two groups (63.4% vs 64.8%, P = 0.18). Of the patients with follow-up, the median number of PVSAs obtained was 1 (range 1–6) in both groups (P = 0.22). Following the release of guidelines, fewer urologists obtained multiple PVSAs (69.8% vs 28.9% pre- and post-2012, P < 0.01). FMPs had a significant but lesser change in the use of multiple PVSAs (47.5% vs 38.4%, P < 0.01). Both groups made appropriate changes in the timing of the first PVSA, but FMPs continued to obtain PVSAs before 8 weeks (15.0% vs 6.5%, P < 0.01). FMPs had a higher rate of positive results in PVSAs obtained after 8 weeks, the earliest recommended by the AUA guidelines (4.1% vs 1.3%, P < 0.01). Significant differences in PVSA utilization between FMPs and urologists were identified and were impacted by the release of AUA guidelines in 2012. In summary, FMPs obtained multiple PVSAs more frequently and continued to obtain PVSAs prior to the 8-week recommendation, suggesting less penetration of AUA guidelines to nonurology specialties. Furthermore, FMPs had more positive results on PVSAs obtained within the recommended window.

Proteomic analysis of seminal plasma from bilateral varicocele patients indicates an oxidative state and increased inflammatory response Manesh Kumar Panner Selvam, Ashok Agarwal, Saradha Baskaran Asian Journal of Andrology 2019 21(6):544-550 Seminal plasma is a rich source of proteins and serves as an ideal sample for proteomic analysis of male infertility. In varicocele-associated infertility, the contributory role of seminal plasma proteins specific to unilateral and bilateral varicocele is not clear. Furthermore, there is a lack of specific protein biomarker to differentiate bilateral from unilateral varicocele. The main objective is to identify the differentially regulated molecular and cellular pathways in bilateral varicocele. Furthermore, we intend to identify seminal plasma biomarkers to differentiate bilateral and unilateral varicocele patients in comparison with fertile healthy men. Global proteomic analysis of seminal plasma proteins has identified the functionality of differentially expressed proteins (DEPs) in varicocele patients. Bioinformatic analysis has revealed response to reactive oxygen species and oxidative stress, and tissue homeostasis as top process pathways that are affected in bilateral varicocele patients compared to fertile healthy men. In comparison with unilateral varicocele patients, inflammatory response pathways were dysregulated, especially interleukin 6 (IL-6) signaling and Janus kinase-signal transducer and activator of transcription (Jak-STAT) pathways, in bilateral varicocele patients, owing to the involvement of underexpressed DEPs. Key DEPs associated with oxidative stress (peroxiredoxin 2; PRDX2), DNA fragmentation (fatty acid synthase; FASN), and inflammatory response (fibronectin 1; FN1) validated by western blot analysis revealed differential expression of these proteins in unilateral and bilateral varicocele groups. Altered expression of DEPs and its association with key processes show that the seminal plasma homeostasis is compromised in bilateral varicocele patients. Furthermore, we propose PRDX2, FASN, and FN1 as potential noninvasive seminal plasma markers for the differentiation of unilateral and bilateral varicocele patients.

Timing of pubertal development in boys born with cryptorchidism and hypospadias: a nationwide cohort study Linn Håkonsen Arendt, Andreas Ernst, Lea Lykke Braskhøj Lauridsen, Nis Brix, Jørn Olsen, Cecilia Høst Ramlau-Hansen Asian Journal of Andrology 2019 21(6):551-556 Pubertal development may be altered in boys with cryptorchidism and hypospadias, but existing knowledge is inconsistent. Therefore, we investigated the association between cryptorchidism and hypospadias and pubertal development in a large cohort study. Boys in the Puberty Cohort, a cohort nested within the Danish National Birth Cohort, were included in this study. Information on cryptorchidism and hypospadias was retrieved from the Danish National Patient Register. From 11 years until 18 years or full pubertal development, information on physical markers of pubertal development was provided biannually, including Tanner stages, axillary hair, acne, voice break, and first ejaculation. In multivariate regression models for interval censored data, the mean (95% confidence intervals [CIs]) differences in months in obtaining the pubertal markers between boys with and without the anomalies were estimated. Among 7698 boys, 196 (2.5%) had cryptorchidism and 60 (0.8%) had hypospadias. Boys with hypospadias experienced first ejaculation and voice break 7.7 (95% CI: 2.5–13.0) months and 4.5 (95% CI: 0.3–8.7) months later than boys without hypospadias. The age at attaining the Tanner stages for gonadal and pubic hair growth was also higher, though not statistically significant. Pubertal development seemed unaffected in boys with mild as well as severe cryptorchidism. In conclusion, hypospadias may be associated with delayed pubertal development, but pubertal development seems unaffected by cryptorchidism. The relation between hypospadias and later pubertal development may be due to the underlying shared in utero risk or genetic factors.

Secreted protein acidic and rich in cysteine (SPARC) induces epithelial-mesenchymal transition, enhancing migration and invasion, and is associated with high Gleason score in prostate cancer Fernanda López-Moncada, María José Torres, Enrique A Castellón, Héctor R Contreras Asian Journal of Andrology 2019 21(6):557-564 Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein highly expressed in bone tissue that acts as a chemoattractant factor promoting the arrival of prostate cancer (PCa) cells to the bone marrow. However, the contribution of SPARC during the early stages of tumor progression remains unclear. In this study, we show that SPARC is highly expressed in PCa tissues with a higher Gleason score. Through stable knockdown and overexpression of SPARC in PC3 and LNCaP cells, respectively, here we demonstrate that endogenous SPARC induces the epithelial-mesenchymal transition (EMT), decreasing E-cadherin and cytokeratin 18 and increasing N-cadherin and vimentin. Moreover, SPARC induces the expression of EMT regulatory transcription factors Snail family transcriptional repressor 1 (Snail), Snail family transcriptional repressor 2 (Slug), and zinc finger E-box binding homeobox 1 (Zeb1). In addition, SPARC knockdown in PC3 cells decreases migration and invasion in vitro, without modifying cell proliferation. Our results indicate that SPARC might facilitate tumor progression by modifying the cellular phenotype in cancer cells.

Multi-center evaluation of oxidation-reduction potential by the MiOXSYS in males with abnormal semen Ashok Agarwal, Manesh Kumar Panner Selvam, Mohamed Arafa, Hiroshi Okada, Sheryl Homa, Aideen Killeen, Basak Balaban, Ramadan Saleh, Abdullah Armagan, Shubhadeep Roychoudhury, Suresh Sikka Asian Journal of Andrology 2019 21(6):565-569 According to the World Health Organization (WHO), oxidative stress (OS) is a significant contributor to male infertility. Seminal OS can be measured by a number of assays, all of which are either costly or time sensitive and/or require large semen volume and complex instrumentation. One less expensive alternative is to quantify the oxidation-reduction potential (ORP) with the MiOXSYS. In this international multi-center study, we assessed whether ORP levels measured by the MiOXSYS could distinguish semen samples that fall within the 2010 WHO normal reference values from those that do not. Semen samples were collected from 2092 patients in 9 countries; ORP was normalized to sperm concentration (mV/106 sperm/ml). Only those samples with a concentration >1 × 106 sperm ml–1 were included. The results showed that 199 samples fell within the WHO normal reference range while the remaining 1893 samples did not meet one or more of the criteria. ORP was negatively correlated with all semen parameters (P < 0.01) except volume. The area under the curve for ORP was 0.765. The ORP cut-off value (1.34 mV/106 sperm/ml) was able to differentiate specimens with abnormal semen parameters with 98.1% sensitivity, 40.6% specificity, 94.7% positive predictive value (PPV) and 66.6% negative predictive value (NPV). When used as an adjunct to traditional semen analysis, ORP levels may help identify altered functional status of spermatozoa caused by OS in cases of idiopathic male infertility and in male partners of couples suffering recurrent pregnancy loss, and thereby directing these men to relevant medical therapies and lifestyle modifications.

Autophagy is increased in cryptorchid testis resulting in abnormal spermatozoa Marina G Yefimova, Antoine Buschiazzo, Agnes Burel, Marie-Therese Lavault, Celine Pimentel, Guilhem Jouve, Sylvie Jaillard, Bernard Jegou, Nicolas Bourmeyster, Celia Ravel Asian Journal of Andrology 2019 21(6):570-576 Autophagy is involved in spermatogenesis by regulating germ cell maturation. This catabolic process increases with hyperthermic conditions to prevent the accumulation of damaged organelles. Cryptorchidism is associated with impairment of germ cell maturation revealed by the presence of immature forms of sperm cells in ejaculates. The aim of the present study was to evaluate the status of autophagy in sperm cells from cryptorchid patients. Semen samples of cryptorchid patients and normozoospermic controls were analyzed by immunocytochemistry and electron microscopy. Autophagy proteins, autophagy-related protein 9 (ATG9) and microtubule-associated protein, 1A/1B-light chain 3 (LC3) were localized by immunocytochemistry on the acrosome and on the equatorial segment of sperm cells. LC3 was also detected in the midpiece of cryptorchid sperm tail. Autophagy substrate p62 protein was present in the acrosome and in the postequatorial segment of sperm in control samples, but not in the cryptorchid ones. Transmission electron microscopy revealed double-membrane-limited autophagosomes in postequatorial part of spermatozoa head and midpiece in cryptorchid samples. Partly degraded mitochondria were frequently discerned in autophagic vacuoles. In conclusion, autophagy is increased in sperm cells from patients with cryptorchid history comparatively to control. Our work provides insights into the role of autophagy in the maturation and survival of human male gametes in pathological conditions. Thus, regulating autophagy could represent a potential way to improve sperm quality in cryptorchid men.

Identification of three novel SRD5A2 mutations in Chinese patients with 5α-reductase 2 deficiency Tong Cheng, Hao Wang, Bing Han, Hui Zhu, Hai-Jun Yao, Shuang-Xia Zhao, Wen-Jiao Zhu, Hua-Ling Zhai, Fu-Guo Chen, Huai-Dong Song, Kai-Xiang Cheng, Yang Liu, Jie Qiao Asian Journal of Andrology 2019 21(6):577-581 In this study, we investigated the genetics, clinical features, and therapeutic approach of 14 patients with 5α-reductase deficiency in China. Genotyping analysis was performed by direct sequencing of PCR products of the steroid 5α-reductase type 2 gene (SRD5A2). The 5α-reductase activities of three novel mutations were investigated by mutagenesis and an in vitro transfection assay. Most patients presented with a microphallus, variable degrees of hypospadias, and cryptorchidism. Eight of 14 patients (57.1%) were initially reared as females and changed their social gender from female to male after puberty. Nine mutations were identified in the 14 patients. p.G203S, p.Q6X, and p.R227Q were the most prevalent mutations. Three mutations (p.K35N, p.H162P, and p.Y136X) have not been reported previously. The nonsense mutation p.Y136X abolished enzymatic activity, whereas p.K35N and p.H162P retained partial enzymatic activity. Topical administration of dihydrotestosterone during infancy or early childhood combined with hypospadia repair surgery had good therapeutic results. In conclusion, we expand the mutation profile of SRD5A2 in the Chinese population. A rational clinical approach to this disorder requires early and accurate diagnosis, especially genetic diagnosis.

Adding a vacuum erection device to regular use of Tadalafil improves penile rehabilitation after posterior urethroplasty Dong-Liang Zhang, Zhong Chen, Fei-Xiang Wang, Jiong Zhang, Hong Xie, Ze-Yu Wang, Yu-Bo Gu, Qiang Fu, Lu-Jie Song Asian Journal of Andrology 2019 21(6):582-586 This study aimed to evaluate whether adding a vacuum erection device (VED) to regular use of Tadalafil could achieve better penile rehabilitation following posterior urethroplasty for pelvic fracture-related urethral injury (PFUI). Altogether, 78 PFUI patients with erectile dysfunction (ED) after primary posterior urethroplasty were enrolled and divided into two treatment groups: VED combined with Tadalafil (Group 1, n = 36) and Tadalafil only (Group 2, n = 42). Changes in penile length, testosterone level, International Index of Erectile Function-5 (IIEF-5) questionnaire, Quality of Erection Questionnaire (QEQ), and nocturnal penile tumescence (NPT) testing were used to assess erectile function before and after 6 months of ED treatment. Results showed that the addition of VED to regular use of Tadalafil preserved more penile length statistically (0.4 ± 0.9 vs −0.8 ± 0.7 cm, P < 0.01). IIEF-5 score and QEQ score in Group 1 were higher than Group 2 (both P < 0.05). After treatment, 21/36 (58.3%) Group 1 patients and 19/42 (45.2%) Group 2 patients could complete vaginal penetration. Group 1 patients also had markedly improved testosterone levels (P = 0.01). Unexpectedly, there was no significant difference in NPT testing between two therapies. For PFUI patients with ED after posterior urethroplasty, the addition of VED to regular use of Tadalafil could significantly improve their conditions – improving erection and increasing penile length – thus increasing patient satisfaction and confidence in penile rehabilitation.

Effect of prolactin on penile erection: a cross-sectional study Zhi-He Xu, Dong Pan, Tong-Yan Liu, Ming-Zhen Yuan, Jian-Ye Zhang, Shan Jiang, Xue-Sheng Wang, Yong Guan, Sheng-Tian Zhao Asian Journal of Andrology 2019 21(6):587-591 Although elevated prolactin levels have been shown to inhibit penile erection, the relationship between prolactin and erection of the penile tip or base has not been extensively researched. We therefore investigated the prolactin's effects on erection of the penile tip and base, with a cross-sectional study of 135 patients with erectile dysfunction, based on scores of ≤21 on the International Index of Erectile Function-5. All patients were tested for nocturnal penile tumescence, blood pressure, serum glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol, testosterone, and progesterone. Univariate and multivariate analyses were used to assess the associations between prolactin levels and erection at the penile tip and base. We found no obvious relationship between erection time at penile tip and prolactin levels, but observed a negative correlation between base erection time and prolactin level (hazard ratio: −2.68; 95% confidence interval [CI]: −5.13–−0.22). With increasing prolactin concentration, multivariate analysis showed obvious reduction in base erection time among patients with normal Rigiscan results (hazard ratio: −3.10; 95% CI: −7.96–1.77; P < 0.05). Our data indicate that prolactin inhibits penile erection, particularly at the penile base. In addition, when the effective erection time of the penile base lasts longer than 10 min, prolactin has a more obvious inhibitory effect on penile base erection.