Pathogenesis Of Male Infertility Research Articles

Insights on Platelet-Derived Growth Factor Receptor α-Positive Interstitial Cells in the Male Reproductive Tract.

Male infertility is a significant factor in approximately half of all infertility cases and is marked by a decreased sperm count and motility. A decreased sperm count is caused by not only a decreased production of sperm but also decreased numbers successfully passing through the male reproductive tract. Smooth muscle movement may play an important role in sperm transport in the male reproductive tract; thus, understanding the mechanism of this movement is necessary to elucidate the cause of sperm transport disorder. Recent studies have highlighted the presence of platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PICs) in various smooth muscle organs. Although research is ongoing, PICs in the male reproductive tract may be involved in the regulation of smooth muscle movement, as they are in other smooth muscle organs. This review summarizes the findings to date on PICs in male reproductive organs. Further exploration of the structural, functional, and molecular characteristics of PICs could provide valuable insights into the pathogenesis of male infertility and potentially lead to new therapeutic approaches.

Splicing Mutation in DNALI1 Causes Male Infertility with Severe Oligoasthenoteratozoospermia in Humans.

Oligo-astheno-teratozoospermia (OAT), which is a common cause of male infertility, can be caused by genetic factors. This study reports on a case of a male patient suffering from infertility concomitant with OAT. Whole-exome sequencing (WES) confirmed the presence of a homozygous variant (NM_003462: c.464-1G > A) in the DNALI1 gene via Sanger sequencing. Immunofluorescence staining demonstrated that the DNALI1 signal was nearly undetectable in the patient's sperm. Bioinformatics analysis revealed that this mutation could reverse the splicing of the exon 4 acceptor splice site. A minigene experiment was performed to verify the mutation and the results confirmed that the mutation disrupted the splicing. Our findings show that this rare mutation in DNALI1 contributes to male infertility and OAT in humans, thereby expanding our understanding of the causes and pathogenesis of male infertility. This knowledge facilitates genetic counseling, clinical diagnosis, and therapeutic development of male infertility.

Anti-sperm Antibody Positivity in Men with Varicocele: A Systematic Review and Meta-Analysis.

Despite the significant role of varicocele in the pathogenesis of male infertility, its association with anti-sperm antibodies (ASA) remains controversial. This systematic review and meta-analysis (SRMA) aims to investigate the frequency of ASA positivity in men with varicocele. This SRMA is conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. We investigated the frequency of ASA positivity in ejaculates or serum of men with varicocele as compared to men without varicocele (controls). A literature search was performed using the Scopus and PubMed databases following the Population Exposure Comparison Outcome, Study Design model. Data extracted from eligible studies were meta-analyzed and expressed as odds ratios (ORs) and confidence intervals (CIs). Out of 151 abstracts identified during the initial screening, 6 articles met the inclusion criteria and were included in the meta-analysis. Using mixed antiglobulin reaction (MAR) assay, 61 out of the 153 (39.8%) patients with varicocele tested positive for ASA in their ejaculates as compared to 22 out of the 129 control subjects (17%, OR=4.34 [95% CI: 1.09-17.28]; p=0.04). Using direct or indirect immunobead test, 30 out of 60 cases diagnosed with varicocele (50%) had shown ASA positivity in their ejaculates as compared to 16 out of 104 controls (15.4%, OR=3.57 [95% CI: 0.81-15.68]; p=0.09). Using enzyme-linked immunosorbent assay (ELISA), out of 89 varicocele patients, 33 (37.1%) tested positive for serum ASA as compared to 9 out of 57 participants in the control group (15.8%, OR=7.87 [95% CI: 2.39-25.89]; p<0.01). This SRMA indicates that ASA positivity is significantly higher among men with varicocele when tested by direct method (MAR) or indirect method (ELISA). This data suggests an immunological pathology in infertile men with varicocele and may have implications for the management of these patients.

A metabolomic perspective on the mechanisms by which environmental pollutants and lifestyle lead to male infertility.

The incidence of male infertility (MI) is rising annually. According to epidemiological studies, environmental pollution (e.g., organic, inorganic, and air pollutants), occupational exposure (e.g., high temperature, organic solvents, and pesticides), and poor lifestyle (e.g., diet, sleep, smoking, alcohol consumption, and exercise) are important non-genetic causative factors of MI. Due to multiple and complex causative factors, the dose-effect relationship, and the uncertainty of pathogenicity, the pathogenesis of MI is far from fully clarified. Recent data show that the pathogenesis of MI can be monitored by the metabolites in serum, seminal plasma, urine, testicular tissue, sperm, and other biological samples. It is considered that these metabolites are closely related to MI phenotypes and can directly reflect the individual pathological and physiological conditions. Therefore, qualitative and quantitative analysis of the metabolome, the related metabolic pathways, and the identification of biomarkers will help to explore the MI-related metabolic problems and provide valuable insights into its pathogenic mechanisms. Here, we summarized new findings in MI metabolomics biomarkers research and their abnormal metabolic pathways triggered by the presented non-genetic risk factors, providing a metabolic landscape of semen and seminal plasma in general MI patients. Then, we compared the similarities and differences in semen and seminal plasma biomarkers between MI patients exposed to environmental and poor lifestyle factors and MI patients in general, and summarized some common biomarkers. We provide a better understanding of the biological underpinnings of MI pathogenesis, which might offer novel diagnostic, prognostic, and precise treatment approaches to MI.

Transcriptomic signatures for human male infertility.

Introduction: Male infertility is a common, complex disorder. A better understanding of pathogenesis and etiology is needed for timely diagnosis and treatment. The aim of this study, therefore, was to identify genes involved in the pathogenesis of idiopathic male infertility based on data from transcriptomic level supported with data from genomic level. Materials and methods: First, we performed whole gene expression analysis in 20 testis biopsy samples of patients with severely impaired (10) and normal spermatogenesis (10). Further, we have performed systematic review of comparable male infertility studies and overlapped the most significantly expressed genes identified in our study with the most differentially expressed genes from selected studies. Gene Ontology analysis and KEGG functional enrichment have been performed with Enrichr analysis tool. Additionally, we have overlapped these genes with the genes where rare variants have been identified previously. Results: In 10 patients with severely impaired spermatogenesis and 10 controls, we identified more than 1,800 differentially expressed genes (p < 0.001). With the systematic review of three previously performed microarray studies that have met inclusion criteria we identified 257 overlapped differentialy expressed genes (144 downregulated and 113 upregulated). Intersection of genes from transcriptomic studies with genes with identified rare variants revealed a total of 7 genes linked with male infertility phenotype (CYP11A1, CYP17A1, RSPH3, TSGA10, AKAP4, CCIN, NDNF). Conclusion: Our comprehensive study highlighted the role of four genes in pathogenesis of male infertility and provided supporting evidence for three promising candidate genes which dysfunction may result in a male infertility disorder.

P-021 A novel SNP in HUWE1 promoter confers increased risk of NOA by affecting the RA/RARα pathway in Chinese individuals

Abstract Study question The present study aimed to investigate the role of HUWE1 in non-obstructive azoospermia (NOA) etiology and germ cell differentiation. Summary answer An SNP mutation in HUWE1 promoter region downregulates HUWE1 expression in NOA patients, the genetic polymorphisms of HUWE1 are related to the pathogenesis of NOA. What is known already HUWE1, a ubiquitin ligase, is crucial to the development of male reproductive system and embryonic development. However, the specific role of HUWE1 in regulating germ cell differentiation is unclear, and clinical evidence for the relationship between HUWE1 and the pathogenesis of male infertility is lacking. Study design, size, duration 190 NOA Chinese patients were recruited and analyzed single nucleotide polymorphisms (SNPs) in HUWE1 gene. Participants/materials, setting, methods Regulation of HUWE1 gene expression by RARα factor was evaluated by performing ChIP assay, EMSA, and siRNA-mediated RARα knockdown. We used C18-4 cells to determine whether HUWE1 participated in RA-mediated RARα signaling and performed luciferase assay, CCK-8 assay, immunofluorescence staining, RT-qPCR, and western blot analysis. The expression level of HUWE1 and RARa was evaluated in clinical samples obtained from NOA or obstructive azoospermia (OA) patients using RT-qPCR. Main results and the role of chance We explored the mechanism by which polymorphism of the HUWE1 promoter leads to spermatogenesis disorders, and focused on the identification of mutations in the SNP site of the HUWE1 regulatory sequence among patients with NOA, which may influence HUWE1 expression. The results of in vitro experiments showed that RARα binds to the HUWE1 promoter region and regulates its expression. However, the regulatory effect of RARα weakened following introduction of the mutation into the HUWE1 regulatory sequence. The expression of spermatogonial differentiation-related gene STRA8 was impaired, and γH2AX foci accumulated following inhibition of HUWE1 gene expression using siRARα. Finally, to determine whether HUWE1 expression was important in patients with NOA, its expression was verified using testicular puncture samples collected from patients with NOA and the results revealed that HUWE1 expression was abnormal (P &amp;lt; 0.01). In addition, RARα expression was significantly downregulated (P &amp;lt; 0.001). Overall, our result support the hypothesis that HUWE1 expression is induced by the RA/RARα signaling pathway and it inhibit γH2AX foci accumulation, thereby considerably promoting sperm differentiation and meiotic prophase. Limitations, reasons for caution The effect of SNPs in HUWE1 on male infertility is further studied in a wider population. Wider implications of the findings Our study of HUWE1 and RA/RARα signaling pathway provides new information on the regulatory mechanism of spermiogenesis, suggesting that SNPs in HUWE1 promoter are etiological factors in patients with NOA and providing a rationale for further drug development to target HUWE1 in these patients. Trial registration number the National Key Research and Development Program of China (2018YFC1003603)

Acetylcholinesterase, pro-inflammatory cytokines, and association of ACHE SNP rs 17228602 with male infertility.

Male infertility is a complex and polygenic reproductive disease. 10-15% of the males are affected by idiopathic infertility conditions. Acetylcholine (ACh), a major neurotransmitter has been reported to play a non-neuronal role as well. Acetylcholinesterase (AChE) is the primary ACh hydrolyzing enzyme whose over or lower expression influence the availability of ACh for physiological roles. The purpose of the study was to find the possible impact and association of acetylcholinesterase, ACHE gene variant rs 17228602, and pro-inflammatory cytokines in clinically diagnosed infertile males. The study includes clinically diagnosed fifty non-infertile (control) and forty-five infertile males. Whole blood AChE enzymatic activity was measured. Genotyping of rs17228602 was carried out from peripheral blood by standard molecular methods. Pro-inflammatory cytokines were determined by the ELISA method. AChE enzyme was found to be significantly elevated in infertile than non-infertile males. ACHE SNP rs17228602 had shown significant association in dominant model (odd ratio = 0.378, 95% CI = 0.157-0.911, p-value 0.046). Pro-inflammatory cytokine IL-1β was notably increased with statistical significance (p ≤0.05) in male infertile patients. The study concludes and speculates that AChE plays role in the pathogenesis of male infertility through the modulation of inflammatory pathways. Further studies in this direction may resolve the idiopathic cases of male infertility. Other variants of ACHE and the association of miRNA for the regulation of AChE in male infertility are suggested for further insight.

THE ROLE OF GENETIC FACTORS IN REPRODUCTIVE DYSFUNCTION IN ADOLESCENTS WITH VARICOCELE

In the pathogenesis of male infertility, up to 30% of cases can be attributed to the role of genetic factors and cause both minor changes in spermatogenesis and absolute dysfunction of the gonads. With varicocele under conditions of testicular ischemia and hypoxia, the expression of various genes responsible for spermatogenesis can be modified. Target. To assess the contribution of genetic factors to the risk of reproductive dysfunction in adolescents with varicocele. Materials and methods. Adolescents with varicocele underwent karyotype analysis, study of deletions of the AZF and CFTR gene loci, and spermogram evaluation. Results. When evaluating the karyotype in adolescents with varicocele, shortening of the long arm of the Y chromosome was detected in 1 case (1%), a study of the AZF locus in three people from the main group (3%) revealed a deletion of sY1291, one person (1%) was diagnosed with a deletion in CFTR gene — Nmdel F508. In the study of spermogram, normozoospermia (52%) was most often diagnosed in adolescents with varicocele, and asthenozoospermia (24%) was diagnosed as pathological changes. Conclusions. 1. The frequency of detection of genetic factors of infertility in adolescents with varicocele does not exceed 5%. 2. The identified genetic variants in the groups of adolescents examined did not lead to impaired spermatogenesis, which allows us to consider the contribution of genetic causes to reproductive dysfunction in varicocele as insignificant.

Nuclear Factor Kappa-B Protein Levels in Sperm of Obese Men with and without Diabetes; Cellular Approach in Male Infertility.

Although the role of obesity and diabetes mellitus (DM) in male infertility is well established, little information about the underlying cellular mechanisms in infertility is available. In this sense, nuclear factor kappa-B (NF-kB) has been recognized as an important regulator in obesity and DM; However, its function in the pathogenesis of male infertility has never been studied in obese or men who suffer from diabetes. Therefore, the main goal of current research is assessing NF-kB existence and activity in ejaculated human spermatozoa considering the obesity and diabetics condition of males. In an experimental study, the ELISA technique was applied to analyze NF-kB levels in sperm of four experimental groups: non-obese none-diabetic men (body mass index (BMI) <25 kg/m2; control group; n=30), obese non-diabetic men (BMI >30 kg/m2; OB group; n=30), non-obese diabetic men (BMI <25 kg/m2; DM group; n=30), and obese diabetic men (BMI >30 kg/m2; OB-DM group; n=30) who were presented to Royan Institute Infertility Center. In addition, protein localization was shown by Immunocytofluorescent assay. Sperm features were also evaluated using CASA. The diabetic men were older than non-diabetic men regardless of obesity status (P=0.0002). Sperm progressive motility was affected by obesity (P=0.035) and type A sperm progressive motility was affected by DM (P=0.034). The concentration of sperm (P=0.013), motility (P=0.025) and morphology (P<0.0001) were altered by obesity × diabetes interaction effects. The NF-kB activity was negatively influenced by the main impact of diabetics (P=0.019). Obesity did not affect (P=0.248) NF-kB activity. Uniquely, NF-kB localized to the midpiece of sperm and post-acrosomal areas. The current study indicated a lower concentration of NF-kB in diabetic men, no effect of obesity on NF-kB was observed yet. Additionally, we revealed the main obesity and diabetes effects, and their interaction effect adversely influenced sperm characteristics.

EFFECT OF VARICOCELE REPAIR ON CONVENTIONAL SPERM PARAMETERS IN INFERTILE PATIENTS WITH CLINICAL VARICOCELE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Varicocele is present in almost 35-40% of men presenting with primary infertility. Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. To the best of our knowledge, only a few systematic reviews and meta-analyses (SRMA) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility using a before-after analytic approach for analyzing 22, 17, and 5 prospective uncontrolled trials, respectively. Indeed, the majority of SRMAs have focused on pregnancy rate as an outcome. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls.

P-021 Increased oxidative stress affects semen quality negatively and is associated with reduced levels of seminal glutathione

Abstract Study question Do increased levels of oxidative stress (OS) and seminal antioxidant affect semen quality? Summary answer Increased OS measured by MiOXSYS negatively affected sperm concentration, motility, and total motile sperm count (TMSC). Reduced levels of seminal glutathione are associated with OS. What is known already The enzymatic seminal antioxidants superoxide dismutase (SOD) and catalase (CAT), and the non-enzymatic antioxidant glutathione possess important roles in the defense against oxidative damage and form the first line of defense against reactive oxygen species (ROS). It is known from the literature, that excessive levels of ROS are highly implicated in the pathogenesis of male infertility. The level of oxidative stress can be estimated by MiOXSYS Analyzer (Aytu BioScience Inc.) expressing the ‘oxidative reduction potential’ (ORP). Assessing ORP is one of the latest advancements in male infertility diagnostics, providing sensitive detection of increased OS in semen. Study design, size, duration This correlation study aims to explore the level of OS in a small cross-section of potentially infertile Danish males. Eighty-one (81) males from the Fertility Clinic at Odense University Hospital delivered a semen sample. The level of OS was compared to semen parameters and levels of SOD, CAT, and glutathione. Participants/materials, setting, methods Semen samples were collected and analyzed according to 2010 WHO criteria (concentration, volume, and %motility). TMSC was included additionally. A direct measure of OS was performed on raw sperm using MiOXSYS. Three assays were applied (Sigma-Aldrich and Abcam) to measure the enzymatic activity of SOD and CAT, and the level of total glutathione in the sperm samples. Spectrophotometric analysis of the absorbance in a plate reader was used to quantify the biochemical level of antioxidants. Main results and the role of chance Results showed that 43.2% of all study participants had increased levels of OS. Statistical analysis revealed a significant correlation (p&amp;lt; 0.01) between increased OS and reduced concentration, motility, and TMSC in the ejaculates. When adjusted for smoke, motility and TMSC were found to be significant (p &amp;lt; 0.05). Adjusting for weekly alcohol intake and body mass index (BMI) did not affect the correlation. Collectively, the results demonstrated that sperm abnormalities are related to increased levels of OS, suggesting OS to be a mediator of male fertility potential. Furthermore, a negative correlation (p&amp;lt; 0.05) was found between the reduced level of seminal glutathione and increased levels of OS. The finding suggests that OS is increased in the spermatozoa when the level of glutathione is low. No significant correlation between OS and reduced SOD or CAT was found. A potential inverse relationship between the effect of SOD on CAT and GSH levels was investigated, but no significant relationship was identified. There were no statistical indications that the level of SOD is associated with the levels of CAT and GSH. Limitations, reasons for caution Morphology was not included as a part of the WHO criteria due to time limitations. DNA fragmentation analysis was not included, but future research should be devoted to this aspect. Wider implications of the findings The findings support a suggestion of an association between high OS levels in semen and reduced semen quality. It was expected that at least 30% of men would show excessive OS in sperm. The study population of the Fertility-Clinic showed higher OS than what was presented in the general population. Trial registration number Not applicable

The genetic causes of male infertility: a Middle East and North Africa perspective.

Male infertility is attributable to 60% of total infertility cases and about 30-50% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.

Multiomics analysis of male infertility

Infertility affects 8-12% of couples globally, and the male factor is a primary cause in ~50% of couples. Male infertility is a multifactorial reproductive disorder, which can be caused by paracrine and autocrine factors, hormones, genes, and epigenetic changes. Recent studies in rodents and most notably in humans using multiomics approach have yielded important insights into understanding the biology of spermatogenesis. Nonetheless, the etiology and pathogenesis of male infertility are still largely unknown. In this review, we summarized and critically evaluated findings based on the use of advanced technologies to compare normal and obstructive azoospermic versus nonobstructive azoospermic men, including whole-genome bisulfite sequencing, single-cell RNA-seq, whole-exome sequencing, and transposase-accessible chromatin using sequencing. It is obvious that the multiomics approach is the method of choice for basic research and clinical studies including clinical diagnosis of male infertility.

Roles of Spermatogonial Stem Cells in Spermatogenesis and Fertility Restoration.

Spermatogonial stem cells (SSCs) are a group of adult stem cells in the testis that serve as the foundation of continuous spermatogenesis and male fertility. SSCs are capable of self-renewal to maintain the stability of the stem cell pool and differentiation to produce mature spermatozoa. Dysfunction of SSCs leads to male infertility. Therefore, dissection of the regulatory network of SSCs is of great significance in understanding the fundamental molecular mechanisms of spermatogonial stem cell function in spermatogenesis and the pathogenesis of male infertility. Furthermore, a better understanding of SSC biology will allow us to culture and differentiate SSCs in vitro, which may provide novel stem cell-based therapy for assisted reproduction. This review summarizes the latest research progress on the regulation of SSCs, and the potential application of SSCs for fertility restoration through in vivo and in vitro spermatogenesis. We anticipate that the knowledge gained will advance the application of SSCs to improve male fertility. Furthermore, in vitro spermatogenesis from SSCs sets the stage for the production of SSCs from induced pluripotent stem cells (iPSCs) and subsequent spermatogenesis.

Mast cell hyperactivity as the factor in the pathogenesis of male infertility

The proportion of men with impaired sperm fertility is increasing every year, which is one of the factors in the decline in fertility and is becoming both a medical and social problem. Modern diagnostic methods make it possible to recognize many factors of male infertility: genetic, endocrine, infectious, extra-genital, etc. However, despite all modern biomedical advances, 1/3 of patients remain with an unrecognized cause (idiopathic) of male infertility. At the same time, we must not forget that most patients from this category do not want to resort to assisted reproductive technologies to realize paternity, and they strive to achieve pregnancy in a natural way. Therefore, the search for the causes of male infertility remains an urgent issue in modern urology field. This article reviews the literature on the role of mast cells in the formation of fibrosis in tissues, including the testis. Mast cells affect the proliferation, functioning and phenotype of fibroblasts put under hypoxic conditions. Fibroblast activation enhances collagen fibrillogenesis. Studies by Russian and foreign scientists have shown that with sperm pathology, the number of mast cells in the connective tissue of the testicle increases sharply. Against the background of an increase in the number of mast cells in the interstitium of the testis, fibrosis of the wall of the convoluted seminiferous tubules increases. Moreover, in severe spermatogenesis disorders (Sertoli cell-only syndrome, Germ cell aplasia), mast cells were found both in the peritubular space and in the lumen of the convoluted seminiferous tubules. Most infertile men have significant amounts of significant amounts of mast cells in their ejaculate. There are sporadic data on the negative correlation between the presence of mast cells in seminal plasma and the concentration and motility of spermatozoa. Conclusion. The negative effect of mast cells on spermatogenesis remains unknown to the end. Mast cells have a high ability to migrate to connective tissue, which levels increase during inflammation, and the production of many mediators, proteases and histamine, cytokines, which can be both a trigger in the formation of sperm pathology and the cause of the formation of fibrosis in the testicle.

Using publicly available transcriptomic data to identify mechanistic and diagnostic biomarkers in azoospermia and overall male infertility

Azoospermia, which is the absence of spermatozoa in an ejaculate occurring due to defects in sperm production, or the obstruction of the reproductive tract, affects about 1% of all men and is prevalent in up to 10–15% of infertile males. Conventional semen analysis remains the gold standard for diagnosing and treating male infertility; however, advances in molecular biology and bioinformatics now highlight the insufficiency thereof. Hence, the need to widen the scope of investigating the aetiology of male infertility stands pertinent. The current study aimed to identify common differentially expressed genes (DEGs) that might serve as potential biomarkers for non-obstructive azoospermia (NOA) and overall male infertility. DEGs across different datasets of transcriptomic profiling of testis from human patients with different causes of infertility/ impaired spermatogenesis and/or azoospermia were explored using the gene expression omnibus (GEO) database. Following the search using the GEOquery, 30 datasets were available, with 5 meeting the inclusion criteria. The DEGs for datasets were identified using limma R packages through the GEO2R tool. The annotated genes of the probes in each dataset were intersected with DEGs from all other datasets. Enriched Ontology Clustering for the identified genes was performed using Metascape to explore the possible connection or interaction between the genes. Twenty-five DEGs were shared between most of the datasets, which might indicate their role in the pathogenesis of male infertility. Of the 25 DEGs, eight genes (THEG, SPATA20, ROPN1L, GSTF1, TSSK1B, CABS1, ADAD1, RIMBP3) are either involved in the overall spermatogenic processes or at specific phases of spermatogenesis. We hypothesize that alteration in the expression of these genes leads to impaired spermatogenesis and, ultimately, male infertility. Thus, these genes can be used as potential biomarkers for the early detection of NOA.

The genetic causes of male infertility: a Middle East and North Africa perspective.

Male infertility is attributable to 50% of total infertility cases and about 30% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.

Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis.

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. 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). 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%). 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.

The peculiarities of hormonal background in boars under correction of reproductive capacity by gadolinium orthovanadate nanoparticles

Determination of the influence of redox nanomaterials on the body of males is of great interest to researchers, because the basis of the pathogenesis of male infertility is oxidative stress. A necessary condition in the development of such drugs is the absence of toxic effects on sexual function. It has been proved that nanomaterials based on oxides of rare earth elements have a positive effect on reproductive capacity and, at the same time, they are not gonadotoxic. A comprehensive approach is of particular importance in order to justify their use as a means of reproductive capacity correction. Taking into account the toxicity parameters the mechanisms of their action need to be studied at the biochemical, morphological and clinical levels. The positive effect of gadolinium orthovanadate nanoparticles on the quality of boar sperm (especially in terms of motility and the number of motile sperm in the ejaculate) with an effective reduction of the oxidative load on the body have been shown. The aim of this study was to determine the effect of these nanoparticles on the hormonal background of males with a decreased reproductive capacity under oxidative stress. Thus, the administration of hydrosol of gadolinium orthovanadate nanoparticles for 14 days revealed a normalization of sex hormones – an increase in total testosterone, in particular, on the 15th day of the study – by 22.6 % (P ˂ 0.01), and on the 30th day – by 77.4 % (P ˂ 0.001) compared with the group of animals before the administration. There was a decrease in the level of 17β-estradiol on the 30th day – by 25.0 % (P ˂ 0.01), which almost reached the values of the control group. A decrease in the content of globulin testosterone-estradiol-binding in boars of the experimental group, in particular, on the 15th day of the experiment – by 13.0 % (P ˂ 0.05), and on the 30th day – by 26.8 % (P ˂ 0.001) was determined, which, in turn, led to an increase in androgen saturation of the animal body – the index of free androgens at the end of the study was 43.2 %. The results are explained by the properties of the nanoparticles. Correcting oxidative stress, they increase the antioxidant potential, thereby normalizing the activity of endocrine glands and ways of regulating the germ-endocrine function of the gonads. The prospect of further research is to elucidate the effect of the correction of decreased reproductive capacity in boars under oxidative stress by nanoparticles of oxides of rare earth elements on the morphological state of the gonads.

Pathogenesis of Autoimmune Male Infertility: Juxtacrine, Paracrine, and Endocrine Dysregulation.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility is often associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, and thus preventing ovum fertilization. Infertility diagnosis requires a mandatory check for the ASAs. The concept of the blood–testis barrier is currently re-formulated, with an emphasis on informational paracrine and juxtacrine effects, rather than simple anatomical separation. The etiology of male infertility includes both autoimmune and non-autoimmune diseases but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter the blood–testis barrier, facilitating ASAs production as well. There are contradictory data on the role of ASAs in the pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to “danger concept” mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism, and hypothyroidism also facilitate ASAs production. The diagnostic value of various ASAs has not yet been clearly attributed, and their cut-levels have not been determined in sera nor in ejaculate. The assessment of the autoimmunity role in the pathogenesis of male infertility is ambiguous, so the purpose of this review is to show the effects of ASAs on the pathogenesis of male infertility.