Male Infertility is a Women\u27s Health Issue-Research and Clinical Evaluation of Male Infertility Is Needed

Infertility is a devastating experience for both partners as they try to conceive. Historically, when a couple could not conceive, the woman has carried the stigma of infertility; however, men and women are just as likely to contribute to the couple\u27s infertility. With the development of assisted reproductive technology (ART), the treatment burden for male and unexplained infertility has fallen mainly on women. Equalizing this burden requires reviving research on male infertility to both improve treatment options and enable natural conception. Despite many scientific efforts, infertility in men due to sperm dysfunction is mainly diagnosed by a semen analysis. The semen analysis is limited as it only examines general sperm properties such as concentration, motility, and morphology. A diagnosis of male infertility rarely includes an assessment of internal sperm components such as DNA, which is well documented to have an impact on infertility, or other components such as RNA and centrioles, which are beginning to be adopted. Assessment of these components is not typically included in current diagnostic testing because available treatments are limited. Recent research has expanded our understanding of sperm biology and suggests that these components may also contribute to the failure to achieve pregnancy. Understanding the sperm\u27s internal components, and how they contribute to male infertility, would provide avenues for new therapies that are based on treating men directly for male infertility, which may enable less invasive treatments and even natural conception

Tubulin nucleotide status controls Sas-4-dependent pericentriolar material recruitment

Regulated centrosome biogenesis is required for accurate cell division and for maintaining genome integrity1. Centrosomes consist of a centriole pair surrounded by a protein network known as pericentriolar material (PCM)1. PCM assembly is a tightly regulated, critical step that determines a centrosome’s size and capability2–4. Here, we report a role for tubulin in regulating PCM recruitment via the conserved centrosomal protein Sas-4. Tubulin directly binds to Sas-4; together they are components of cytoplasmic complexes of centrosomal proteins5,6. A Sas-4 mutant, which cannot bind tubulin, enhances centrosomal protein complex formation and has abnormally large centrosomes with excessive activity. These suggest that tubulin negatively regulates PCM recruitment. Whereas tubulin-GTP prevents Sas-4 from forming protein complexes, tubulin-GDP promotes it. Thus, tubulin’s regulation of PCM recruitment depends on its GTP/GDP-bound state. These results identify a role for tubulin in regulating PCM recruitment independent of its well-known role as a building block of microtubules7. Based on its guanine bound state, tubulin can act as a molecular switch in PCM recruitment

Sperm centriole assessment identifies male factor infertility in couples with unexplained infertility - a pilot study

Unexplained infertility affects about one-third of infertile couples and is defined as the failure to identify the cause of infertility despite extensive evaluation of the male and female partners. Therefore, there is a need for a multiparametric approach to study sperm function. Recently, we developed a Fluorescence-Based Ratiometric Analysis of Sperm Centrioles (FRAC) assay to determine sperm centriole quality. Here, we perform a pilot study of sperm from 10 fertile men and 10 men in couples with unexplained infertility, using three centriolar biomarkers measured at three sperm locations from two sperm fractions, representing high and low sperm quality. We found that FRAC can identify men from couples with unexplained infertility as the likely source of infertility. Higher quality fractions from 10 fertile individuals were the reference population. All 180 studied FRAC values in the 10 fertile individuals fell within the reference population range. Eleven of the 180 studied FRAC values in the 10 infertile patients were outliers beyond the 95% confidence intervals (P = 0.0008). Three men with unexplained infertility had outlier FRAC values in their higher quality sperm fraction, while four had outlier FRAC values in their lower quality sperm fraction (3/10 and 4/10, P = 0.060 and P = 0.025, respectively), suggesting that these four individuals are infertile due, in part, to centriolar defects. We propose that a larger scale study should be performed to determine the ability of FRAC to identify male factor infertility and its potential contribution to sperm multiparametric analysis

A dynamic basal complex modulates mammalian sperm movement

Centrioles are ancient organelles with a conserved architecture and their rigidity is thought to restrict microtubule sliding. Here authors show that, in mammalian sperm, the atypical distal centriole and its surrounding atypical pericentriolar matrix form a dynamic basal complex that facilitates a cascade of internal sliding deformations, coupling tail beating with asymmetric head kinking

Technical Aspects and Clinical Limitations of Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

PURPOSE: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. MATERIALS AND METHODS: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. RESULTS: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). CONCLUSIONS: This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial

Artificial intelligence in andrology: From Semen Analysis to Image Diagnostics

Artificial intelligence (AI) in medicine has gained a lot of momentum in the last decades and has been applied to various fields of medicine. Advances in computer science, medical informatics, robotics, and the need for personalized medicine have facilitated the role of AI in modern healthcare. Similarly, as in other fields, AI applications, such as machine learning, artificial neural networks, and deep learning, have shown great potential in andrology and reproductive medicine. AI-based tools are poised to become valuable assets with abilities to support and aid in diagnosing and treating male infertility, and in improving the accuracy of patient care. These automated, AI-based predictions may offer consistency and efficiency in terms of time and cost in infertility research and clinical management. In andrology and reproductive medicine, AI has been used for objective sperm, oocyte, and embryo selection, prediction of surgical outcomes, cost-effective assessment, development of robotic surgery, and clinical decision-making systems. In the future, better integration and implementation of AI into medicine will undoubtedly lead to pioneering evidence-based breakthroughs and the reshaping of andrology and reproductive medicine

Technical aspects and clinical limitations of sperm DNA fragmentation testing in male infertility: A global survey, current guidelines, and expert recommendations

Purpose Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. Materials and Methods Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. Results The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). Conclusions This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial

Controversy and consensus on the management of elevated sperm DNA fragmentation in male infertility: A global survey, current guidelines, and expert recommendations

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

Rapid Evolution of Sperm Produces Diverse Centriole Structures that Reveal the Most Rudimentary Structure Needed for Function

Centrioles are ancient subcellular protein-based organelles that maintain a conserved number and structure across many groups of eukaryotes. Centriole number (two per cells) is tightly regulated; each pre-existing centriole nucleates only one centriole as the cell prepares for division. The structure of centrioles is barrel-shaped, with a nine-fold symmetry of microtubules. This organization of microtubules is essential for the ancestral function of centriole–cilium nucleation. In animal cells, centrioles have gained an additional role: recruiting pericentriolar material (PCM) to form a centrosome. Therefore, it is striking that in animal spermatozoa, the centrioles have a remarkable diversity of structures, where some are so anomalous that they are referred to as atypical centrioles and are barely recognizable. The atypical centriole maintains the ability to form a centrosome and nucleate a new centriole, and therefore reveals the most rudimentary structure that is needed for centriole function. However, the atypical centriole appears to be incapable of forming a cilium. Here, we propose that the diversity in sperm centriole structure is due to rapid evolution in the shape of the spermatozoa head and neck. The enhanced diversity may be driven by a combination of direct selection for novel centriole functions and pleiotropy, which eliminates centriole properties that are dispensable in the spermatozoa function

The Centrosome: Conclusions and Perspectives

The centrosome consists of two centrioles surrounded by pericentriolar material [...