'Intracytoplasmic sperm injection (ICSI) paradox' and 'andrological ignorance': AI in the era of fourth industrial revolution to navigate the blind spots.

The quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and 'andrological ignorance' - a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by 'andrological ignorance.' We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.

A proof-of-concept study on endoscopic ultrasound-guided biopsy of detrusor muscle in porcine bladders.

Introduction: Conventionally, we rely on transurethral resection of bladder tumour (TURBT) for local staging of muscle-invasive bladder cancer (MIBC). However, the procedure is limited by its staging inaccuracy which may delay the definitive treatment of MIBC. Methods: We conducted a proof-of concept study on endoscopic ultrasound (EUS)-guided biopsy of detrusor muscle in porcine bladders. Five porcine bladders were used in this experiment. Upon EUS, four layers of tissue including the mucosa (hypoechoic), submucosa (hyperechoic), detrusor muscle (hypoechoic) and serosa (hyperechoic) could be identified. Results: A total of 37 EUS-guided biopsies were taken from 15 sites (three sites per bladder), and the mean number of biopsies taken from each site was 2.47±0.64. Among the 37 biopsies, 30 of them (81.1%) obtained detrusor muscle in the biopsy specimen. For the per biopsy site analysis, detrusor muscle was obtained in 73.3% if only one biopsy was taken, and 100% if two or more biopsies were taken from the same biopsy site. Overall, detrusor muscle was successfully obtained from all 15 biopsy sites (100%). No bladder perforation was observed throughout all biopsy processes. Conclusion: EUS-guided biopsy of the detrusor muscle could be performed during the initial cystoscopy session, thus expediting the histological diagnosis and subsequent treatment of MIBC.

Consensus and Diversity in the Management of Varicocele for Male Infertility: Results of a Global Practice Survey and Comparison with Guidelines and Recommendations.

PURPOSE: Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility. MATERIALS AND METHODS: Sixty practicing urologists/andrologists from 23 countries contributed 382 multiple-choice-questions pertaining to varicocele management. These were condensed into an online questionnaire that was forwarded to clinicians involved in male infertility management through direct invitation. The results were analyzed for disagreement and agreement in practice patterns and, compared with the latest guidelines of international professional societies (American Urological Association [AUA], American Society for Reproductive Medicine [ASRM], and European Association of Urology [EAU]), and with evidence emerging from recent systematic reviews and meta-analyses. Additionally, an expert opinion on each topic was provided based on the consensus of 16 experts in the field. RESULTS: The questionnaire was answered by 574 clinicians from 59 countries. The majority of respondents were urologists/uro-andrologists. A wide diversity of opinion was seen in every aspect of varicocele diagnosis, indications for repair, choice of technique, management of sub-clinical varicocele and the role of VR in azoospermia. A significant proportion of the responses were at odds with the recommendations of AUA, ASRM, and EAU. A large number of clinical situations were identified where no guidelines are available. CONCLUSIONS: This study is the largest global survey performed to date on the clinical management of varicocele for male infertility. It demonstrates: 1) a wide disagreement in the approach to varicocele management, 2) large gaps in the clinical practice guidelines from professional societies, and 3) the need for further studies on several aspects of varicocele management in infertile men.

Oxidative Stress and Varicocele-Associated Male Infertility.

Despite being regarded as one of the most common causes of male subfertility, the pathophysiology of varicocele remains largely unknown. Recently, oxidative stress (OS) is proposed to be the mediator in how varicocele may negatively impact fertility. The imbalance of reactive oxygen species (ROS) and seminal antioxidants results in damage to sperm DNA and lipid membrane. There is evidence demonstrating higher OS level in men with varicocele which is also positively correlated with clinical grading of varicocele. Moreover, a number of studies have revealed the negative correlation between OS and conventional semen parameters. Furthermore, various interventions have shown their potential in alleviating OS in men with varicocele-associated infertility. Although direct evidence on improving pregnancy rate is not available at the moment, varicocelectomy has demonstrated promising results in relieving OS. Oral antioxidants represent another option with a favourable safety profile. The supplement can be used alone or as adjunct to varicocelectomy. However, most of the studies are hampered by heterogenous dose regime and high-level evidence is lacking.

Antisperm Antibody Testing: A Comprehensive Review of Its Role in the Management of Immunological Male Infertility and Results of a Global Survey of Clinical Practices.

Antisperm antibodies (ASA), as a cause of male infertility, have been detected in infertile males as early as 1954. Multiple causes of ASA production have been identified, and they are due to an abnormal exposure of mature germ cells to the immune system. ASA testing (with mixed anti-globulin reaction, and immunobead binding test) was described in the WHO manual 5th edition and is most recently listed among the extended semen tests in the WHO manual 6th edition. The relationship between ASA and infertility is somewhat complex. The presence of sperm agglutination, while insufficient to diagnose immunological infertility, may indicate the presence of ASA. However, ASA can also be present in the absence of any sperm agglutination. The andrological management of ASA depends on the etiology and individual practices of clinicians. In this article, we provide a comprehensive review of the causes of ASA production, its role in immunological male infertility, clinical indications of ASA testing, and the available therapeutic options. We also provide the details of laboratory procedures for assessment of ASA together with important measures for quality control. Additionally, laboratory and clinical scenarios are presented to guide the reader in the management of ASA and immunological male infertility. Furthermore, we report the results of a recent worldwide survey, conducted to gather information about clinical practices in the management of immunological male infertility.

Sperm Vitality and Necrozoospermia: Diagnosis, Management, and Results of a Global Survey of Clinical Practice.

Sperm vitality testing is a basic semen examination that has been described in the World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen from its primary edition, 40 years ago. Several methods can be used to test sperm vitality, such as the eosin-nigrosin (E-N) stain or the hypoosmotic swelling (HOS) test. In the 6th (2021) edition of the WHO Laboratory Manual, sperm vitality assessment is mainly recommended if the total motility is less than 40%. Hence, a motile spermatozoon is considered alive, however, in certain conditions an immotile spermatozoon can also be alive. Therefore, the differentiation between asthenozoospermia (pathological decrease in sperm motility) and necrozoospermia (pathological decrease in sperm vitality) is important in directing further investigation and management of infertile patients. The causes leading to necrozoospermia are diverse and can either be local or general, testicular or extra-testicular. The andrological management of necrozoospermia depends on its etiology. However, there is no standardized treatment available presently and practice varies among clinicians. In this study, we report the results of a global survey to understand current practices regarding the physician order of sperm vitality tests as well as the management practices for necrozoospermia. Laboratory and clinical scenarios are presented to guide the reader in the management of necrozoospermia with the overall objective of establishing a benchmark ranging from the diagnosis of necrozoospermia by sperm vitality testing to its clinical management.

A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility.

PURPOSE: The use of antioxidants is common practice in the management of infertile patients. However, there are no established guidelines by professional societies on antioxidant use for male infertility. MATERIALS AND METHODS: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility. RESULTS: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3-6 months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician's age, geographic origin, experience or training in male infertility. CONCLUSIONS: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide understanding of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.

Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence.

It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of male infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in male infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in male infertility. The current systematic review on antioxidants and male infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic male infertility, as well as in cases of altered semen quality.

The Use of Testicular Sperm for Intracytoplasmic Sperm Injection in Patients with High Sperm DNA Damage: A Systematic Review.

The advent of intracytoplasmic sperm injection (ICSI) has changed the human reproduction landscape by overcoming several limitations related to both male and female infertility factors. However, despite the development of new technologies, the live-birth rate with ICSI has not exceeded 30%. In order to improve assisted reproductive technology outcomes, advanced sperm function analysis have gained increased attention and the effects of sperm DNA fragmentation (SDF) on assisted reproduction success are being extensively studied. Utilizing ejaculated sperm with an elevated SDF has been found to result in poor ICSI outcomes. Furthermore, studies have reported that testicular sperm has lower SDF level, when compared to ejaculated sperm. This has led a number of clinicians world-wide to offer testicular sperm retrieval for ICSI in non-azoospermic males with high SDF. This practice has remained controversial due to lack of high quality evidence.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.

Male infertility.

It is estimated that infertility affects 8-12% of couples globally, with a male factor being a primary or contributing cause in approximately 50% of couples. Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. Many health conditions can affect male fertility, which underscores the need for a thorough evaluation of patients to identify treatable or reversible lifestyle factors or medical conditions. Although semen analysis remains the cornerstone for evaluating male infertility, advanced diagnostic tests to investigate sperm quality and function have been developed to improve diagnosis and management. The use of assisted reproductive techniques has also substantially improved the ability of couples with infertility to have biological children. This Seminar aims to provide a comprehensive overview of the assessment and management of men with infertility, along with current controversies and future endeavours.

A knotted ureteral stent.

The use of ureteral stent has became an integral part of urological practice. However, its use is not without complications. Stenting knotting represents a rare complication but can be difficult to manage, with less than 30 cases reported in the literature. We report a case in which a complete knot was found in the proximal coil of an indwelling ureteral stent. The knotted stent was untied and removed successfully by ureteroscopy under fluoroscopic guidance.

Sperm DNA Fragmentation: A New Guideline for Clinicians.

Sperm DNA integrity is crucial for fertilization and development of healthy offspring. The spermatozoon undergoes extensive molecular remodeling of its nucleus during later phases of spermatogenesis, which imparts compaction and protects the genetic content. Testicular (defective maturation and abortive apoptosis) and post-testicular (oxidative stress) mechanisms are implicated in the etiology of sperm DNA fragmentation (SDF), which affects both natural and assisted reproduction. Several clinical and environmental factors are known to negatively impact sperm DNA integrity. An increasing number of reports emphasizes the direct relationship between sperm DNA damage and male infertility. Currently, several assays are available to assess sperm DNA damage, however, routine assessment of SDF in clinical practice is not recommended by professional organizations. This article provides an overview of SDF types, origin and comparative analysis of various SDF assays while primarily focusing on the clinical indications of SDF testing. Importantly, we report four clinical cases where SDF testing had played a significant role in improving fertility outcome. In light of these clinical case reports and recent scientific evidence, this review provides expert recommendations on SDF testing and examines the advantages and drawbacks of the clinical utility of SDF testing using Strength-Weaknesses-Opportunities-Threats (SWOT) analysis.

Surgical training for anatomical endoscopic enucleation of the prostate.

Anatomical endoscopic enucleation of the prostate has been proposed as a potentially superior benign prostatic hyperplasia surgery than conventional transurethral resection of prostate. However, the learning curve of the procedure is steep, hence limiting its generalisability worldwide. In order to overcome the learning curve, a proper surgical training is extremely important. This review article discussed about various aspects of surgical training in anatomical endoscopic enucleation of the prostate. In summary, no matter what surgical technique or energy modality you use, the principle of anatomical enucleation should be followed. When one starts to perform prostate enucleation, a 50 to 80 g prostate appears to be the 'best case' to begin with. Mentorship is extremely important to shorten the learning curve and to prevent drastic complications from the procedure. A proficiency-based progression training programme with the use of simulation and training models should be the best way to teach and learn about prostate enucleation. Enucleation ratio efficacy is the preferred measure for assessing skill level and learning curve of prostate enucleation. Morcellation efficiency is commonly used to assess morcellation performance, but the importance of safety rather than efficiency must be emphasised.

Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility.

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

Sperm DNA damage and its impact on male reproductive health: a critical review for clinicians, reproductive professionals and researchers.

Introduction: Sperm DNA damage is the major molecular cause of male infertility, which has a negative effect on reproductive outcomes in couples. Sperm DNA damage originates either during production/maturation or transport of spermatozoa through male genital tract. Though several assays have been used to assess the sperm chromatin integrity and sperm DNA fragmentation (SDF), routine application of SDF testing in semen analysis is generally not reinforced by professional societies. SDF testing is now emerging as a valuable tool and recent clinical practice guidelines (CPG) published by the Society for Translational Medicine recommends SDF testing in various clinical scenarios. Areas covered: This review discusses the origin and factors contributing to sperm DNA damage, the molecular changes, especially proteomic alterations caused due to SDF, risk factors associated with SDF, methods used to analyze SDF, clinical implications of SDF, and CPG recommendations for SDF testing. Expert opinion: Recent clinical practice recommendations suggest the potential role of SDF testing in specific clinical scenarios. This would expand the horizon of SDF testing globally as a prognostic and diagnostic tool in various male infertility scenarios and their treatment management.

Indications and outcomes of varicocele repair.

Varicoceles exert deleterious effect on testicular function. The condition has been associated with male infertility, testicular hypotrophy and pain. These comprises the common indications for varicocele repair currently. Significant improvement in semen parameters and pregnancy outcomes had been suggested by reports decades ago. However, selection of the best candidates remains an issue since not all patients respond positively to treatment. Consensus has been reached in recent decade after the publication of a series of meta-analyses. Significant improvement in pregnancy outcomes were reported in patients with clinical varicocele and abnormal semen parameters. Varicocelectomy in adolescents with testicular hypotrophy was supported by the positive implication on catch-up growth and semen parameters. However, little is known about the treatment effect of adolescence varicocelectomy on long term fertility and paternity rate. Recent studies on outcome of varicocele repair for pain consistently demonstrated a resolution rate of approximately 90% and support varicocele-associated pain as an indication for surgery. Alternate indications for varicocele repair have been proposed in recent decade. Despite the encouraging preliminary data, most studies were uncontrolled retrospective series. Although varicocelectomy may not obviate the need for assisted reproductive techniques in patients with non-obstructive azoospermia, it potentially increases sperm retrieval rate. The significant increase in serum testosterone after varicocelectomy in patients with androgen deficiency may open an alternative treatment for hypogonadism. The adjunctive role of varicocelectomy before assisted reproduction and the significant decrease in sperm DNA fragmentation after varicocele repair deserve further well-designed controlled studies.

A newly developed porcine training model for transurethral piecemeal and en bloc resection of bladder tumour.

PURPOSE: The Asian Urological Surgery Training & Education Group (AUSTEG) has been established to provide training and education to young urologists in Asia. We developed and validated a porcine bladder training model for transurethral resection of bladder tumour (TURBT). METHODS: Urology residents and specialists were invited to test the training model. They were asked to complete a pre-task questionnaire, to perform piecemeal and en bloc resection of 'bladder tumours' within the training model, and to complete a post-task questionnaire afterwards. Their performances were assessed by faculty members of the AUSTEG. For the face validity, a pre-task questionnaire consisting of six statements on TURBT and the training model were set. For the content validity, a post-task questionnaire consisting of 14 items on the details of the training model were set. For the construct validity, a Global Rating Scale was used to assess the participants' performances. The participants were stratified into two groups (junior surgeons and senior surgeons groups) according to their duration of urology training. RESULTS: For the pre-task questionnaire, a mean score of ≥ 4.0 out of 5.0 was achieved in 5 out of 6 statements. For the post-task questionnaire, a mean score of ≥ 4.5 out of 5.0 was achieved in every item. For the Global Rating Scale, the senior surgeons group had higher scores than the junior surgeons group in 8 out of 11 items as well as the total score. CONCLUSION: A porcine TURBT training model has been developed, and its face, content and construct validity has been established.