Purpose: There are no published examples of a global online research collaborative in andrology. We describe the development, profile and member characteristics of the first consortium of this type, the Global Andrology Forum (GAF). Materials and Methods: An online survey sent to all GAF members collected demographic information (sex, age, experience, academic title, degrees, country, specialty, profession). It also tapped data on members’ characteristics e.g., skills in research, software and statistics; preferred activities; time commitments; expected roles; and interest in participating in research, in GAF’s scientific activities and collaborative online research. The findings were analyzed and tabulated. We outline members’ demographic and professional characteristics and scientific achievements to date. A narrative approach outlined GAF’s structure and functioning. Results: A total of 418 out of 540 members completed the survey and were included in the analysis (77.4% response rate). The sample comprised mainly urologists (34.2%) and a third of the respondents had practiced for >15 years (33.3%). Up to 86.1% of the members expressed interest in being actively engaged in writing scientific articles. A third of the sample (37.1%) could dedicate 4 to 6 hours/week. Few respondents reported skills in statistics and artwork (2.6% and 1.9% respectively). Members were assigned to specific roles based on their expertise and experiences. Collaborative working ensured the timely completion of projects while maintaining quality. For outcomes, GAF published 29 original articles within one year of its creation, with authors from 48 countries spanning topics that included varicocele, sperm DNA damage, oxidative stress, semen analysis and male infertility, oocyte/embryo, and laboratory issues of assisted reproductive technique (ART) and male infertility evaluation. Conclusions GAF is a successful global online andrology research model. A healthy number of scientific articles have been published. Given such effectiveness, adopting the GAF model could be useful for other disciplines that wish to create and coordinate successful international online research groups.

Purpose: Systematic reviews and meta-analyses (SRMAs) are used to generate evidence-based guidelines. Although the number of SRMAs published in the literature has increased dramatically in the last decade, the training and the experience of the researchers performing the SRMAs are usually not explained in the SRMAs’ methodology, and this may be a source of bias. Although some studies pointed out the need for quality control of SRMAs and training in proper statistical methods, to the best of our knowledge, no study has reported the importance of training the researchers that conduct the SRMAs. The aim of this study is to describe a training program designed to impart the essential knowledge and skills required for the conduct of an SRMA and to assess the need for, and outcome of, such a training. Materials and Methods: Researchers were trained for use of Scopus, study eligibility, assessment of the quality of evidence (QoE) through the Cambridge Quality Checklist for observational studies, as well as the Cochrane Risk of Bias tool, the Consolidated Standards of Reporting Trials (CONSORT) guidelines, and the Jadad score for randomized controlled trials (RCTs), Population, Intervention, Comparison, Outcome (PICO) questions and data extraction. A total of 35 of them were approved to join a planned SRMA. At the end of the SRMA, they were administered 43 multiple-choice questions (MCQs) on demographics, motivation for participation in the SRMA, self-perceived change in knowledge before and after conducting the SRMA, and self-assessment of performance. The senior researchers then revised the spreadsheet of the SRMA and, based on the mistakes found, organized a training focused on the correct assessment of the study design, where 43 researchers (9 joined midway) and 11 trainees with no experience in conducting SRMA attended. They all were tested through a 5 MCQ assessment that was administered before and after the training. Those scoring poorly were re-trained and re-tested, and only those scoring satisfactorily were admitted to further SRMAs. Results: Approximately 54.3% of the participants were medical doctors (MD), 31.4% were urologists and 48.6% had previous experience with SRMAs. Joining an international collaborative study was the main motivation, chosen by 19.7% of researchers. The results of the self-perceived change in knowledge showed a significant improvement in the use of Scopus, checklists for QoE, PICO questions, data required to perform a meta-analysis, and critical reading of scientific articles. Also, the majority of the researchers ranked the quality of their work as high. The pre-test results of the 5 MCQ showed a low score, which was not different from that achieved by a group of fresh trainees (median, 2; IQR 1–3 vs. median, 1; IQR, 1–2; p=0.3). Post-training there was significant improvement in both groups (researchers: median, 4; IQR, 3–5 vs. median, 2; IQR, 1–3; p<0.001; trainees: median, 4; IQR, 3–4 vs. median, 1; IQR, 1–2; p=0.02). Out of the 44 researchers, 12 (27.3%) scored poorly (≤3). After re-training, all of them scored satisfactorily (>3) and were admitted to subsequent SRMAs. Conclusions At the end of our model, 100% of researchers participating in this study were validated to be included in a meta-analysis. This validation required the involvement of the MT, two meetings, a self-evaluation survey, and one or two sets of objective tests with explanations and corrections. Our results indicate that even well-trained clinicians are naïve when it comes to the methodology of SRMA. All the researchers performing an SRMA need comprehensive training that must cover each aspect of the SRMA methodology. This paper provides a replicable training program that could be used by other investigators to train the researchers to perform high-quality SRMAs.

There have been many significant scientific advances in the diagnostics and treatment modalities in the field of male infertility in recent decades. Examples of these include assisted reproductive technologies, sperm selection techniques for intracytoplasmic sperm injection, surgical procedures for sperm retrieval, and novel tests of sperm function. However, there is certainly a need for new developments in this field. In this review, we discuss advances in the management of male infertility, such as seminal oxidative stress testing, sperm DNA fragmentation testing, genetic and epigenetic tests, genetic manipulations, artificial intelligence, personalized medicine, and telemedicine. The role of the reproductive urologist will continue to expand in future years to address different topzics related to diverse questions and controversies of pathophysiology, diagnosis, and therapy of male infertility, training researchers and physicians in medical and scientific research in reproductive urology/ andrology, and further development of andrology as an independent specialty.

Infertility affects nearly 186 million people worldwide and the male partner is the cause in about half of the cases. Meta-regression data indicate an unexplained decline in sperm concentration and total sperm count over the last four decades, with an increasing prevalence of male infertility. This suggests an urgent need to implement further basic and clinical research in Andrology. Andrology developed as a branch of urology, gynecology, endocrinology, and, dermatology. The first scientific journal devoted to andrological sciences was founded in 1969. Since then, despite great advancements, andrology has encountered several obstacles in its growth. In fact, for cultural reasons, the male partner has often been neglected in the diagnostic and therapeutic workup of the infertile couple. Furthermore, the development of assisted reproductive techniques (ART) has driven a strong impression that this biotechnology can overcome all forms of infertility, with a common belief that having a spermatozoon from a male partner (a sort of sperm donor) is all that is needed to achieve pregnancy. However, clinical practice has shown that the quality of the male gamete is important for a successful ART outcome. Furthermore, the safety of ART has been questioned because of the high prevalence of comorbidities in the offspring of ART conceptions compared to spontaneous conceptions. These issues have paved the way for more research and a greater understanding of the mechanisms of spermatogenesis and male infertility. Consequently, numerous discoveries have been made in the field of andrology, ranging from genetics to several “omics” technologies, oxidative stress and sperm DNA fragmentation, the sixth edition of the WHO manual, artificial intelligence, management of azoospermia, fertility in cancers survivors, artificial testis, 3D printing, gene engineering, stem cells therapy for spermatogenesis, and reconstructive microsurgery and seminal microbiome. Nevertheless, as many cases of male infertility remain idiopathic, further studies are required to improve the clinical management of infertile males. A multidisciplinary strategy involving both clinicians and scientists in basic, translational, and clinical research is the core principle that will allow andrology to overcome its limits and reach further goals. This state-of-the-art article aims to present a historical review of andrology, and, particularly, male infertility, from its “Middle Ages” to its “Renaissance”, a golden age of andrology.

Purpose: Seminal oxidative stress (OS) is a recognized factor potentially associated with male infertility, but the efficacy of antioxidant (AOX) therapy is controversial and there is no consensus on its utility. Primary outcomes of this study were to investigate the effect of AOX on spontaneous clinical pregnancy, live birth and miscarriage rates in male infertile patients. Secondary outcomes were conventional semen parameters, sperm DNA fragmentation (SDF) and seminal OS. Materials and Methods: Literature search was performed using Scopus, PubMed, Ovid, Embase, and Cochrane databases.Only randomized controlled trials (RCTs) were included and the meta-analysis was conducted according to PRISMA guidelines. Results: We assessed for eligibility 1,307 abstracts, and 45 RCTs were finally included, for a total of 4,332 infertile patients.We found a significantly higher pregnancy rate in patients treated with AOX compared to placebo-treated or untreated controls, without significant inter-study heterogeneity. No effects on live-birth or miscarriage rates were observed in four studies.A significantly higher sperm concentration, sperm progressive motility, sperm total motility, and normal sperm morphology was found in patients compared to controls. We found no effect on SDF in analysis of three eligible studies. Seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde acid was significantly lower in patients than controls. These results did not change after exclusion of studies performed following varicocele repair. Conclusions The present analysis upgrades the level of evidence favoring a recommendation for using AOX in male infertility to improve the spontaneous pregnancy rate and the conventional sperm parameters. The failure to demonstrate an increase in live-birth rate, despite an increase in pregnancy rates, is due to the very few RCTs specifically assessing the impact of AOX on live-birth rate. Therefore, further RCTs assessing the impact of AOX on live-birth rate and miscarriage rate, and SDF will be helpful.

Purpose: Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA). Materials and Methods: A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD). Results: Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD −1.125, 95% confidence interval [CI] −1.410, −0.840; p<0.0001) with high inter-study heterogeneity (I2=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD −1.014, 95% CI −1.263, −0.765; p<0.0001, and SMD −1.495, 95% CI −2.116, −0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD −2.197, 95% CI −3.187, −1.207; p<0.0001), sperm chromatin structure assay (SMD −0.857, 95% CI −1.156, −0.559; p<0.0001) or TUNEL (SMD −1.599, 95% CI −2.478, −0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD −2.450, 95% CI −3.903 to −0.997, p=0.001) with high inter-study heterogeneity (I2=93.7%). Conclusions Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.

Humans ; Semen ; Semen Analysis ; Sperm Motility ; World Health Organization

Cryptorchidism is one of the most frequent causes of nonobstructive azoospermia (NOA) in adulthood. Although it is well known that spermatogenesis is more impaired in bilateral than in unilateral cryptorchidism, previous studies have only described small cohorts or inhomogeneous population. Consequently, we analyzed a cohort of 225 men with only a history of cryptorchidism as sole etiopathogenetic factor for NOA, and compared testicular sperm extraction (TESE) outcomes between men with bilateral versus unilateral cryptorchidism. Our results show no difference in follicle-stimulating hormone (FSH) levels and testicular volumes between men with a history of bilateral cryptorchidism compared to unilateral cryptorchidism (median: 21.3 IU l^-1 vs 19.3 IU l^-1, P = 0.306; and 7.2 ml vs 7.9 ml, P = 0.543, respectively). In addition, sperm retrieval rates were similar (66.2% vs 60.0%, P = 0.353). Using multivariate analysis, we have found that only a low inhibin B level (above the assay's detection limit) was positively associated with successful sperm retrieval (P < 0.05). Regarding intracytoplasmic sperm injection outcomes, we found that cumulative pregnancy rate and live birth rate per cycle were not statistically different between the two groups (17.4% vs 27.8%, P = 0.070; and 16.1% vs 26.4%, P = 0.067, respectively). Unexpectedly, there was no significant difference in hormonal profiles (FSH, luteinizing hormone [LH], testosterone, and inhibin B levels) and TESE outcomes between unilateral versus bilateral cryptorchidism. This suggests that a history of unilateral cryptorchidism could reflect a bilateral testicular impairment. Interestingly, inhibin B level might be a predictor of successful TESE.
Adult ; Azoospermia/etiology* ; Cryptorchidism/complications* ; Humans ; Male ; Retrospective Studies ; Sperm Retrieval ; Treatment Outcome

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls. Materials and Methods: A literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies). Results: A total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I2=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I2=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I2=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I2=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I2=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I2=89.7%). Conclusions This study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies’ practice recommendations favoring VR to improve conventional semen parameters in infertile men.

Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and Methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. Results: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4–6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.