Y-chromosome microdeletions, particularly in the azoospermia factor c (AZFc) region, are a common genetic cause of male infertility. This study evaluates sperm retrieval rates (SRRs) and testicular histology across age groups in men with isolated AZFc deletions. We identified men with isolated complete AZFc microdeletions who underwent microdissection testicular sperm extraction from 2000 to 2024. Genitourinary pathology reports categorized histology as Sertoli cell-only, tubular atrophy, maturation arrest, or hypospermatogenesis. χ2 tests compared histology and SRR. Multivariable logistic regression assessed factors associated with successful sperm retrieval. Of 1473 patients who underwent Y-chromosome microdeletion testing, 72 with isolated AZFc microdeletions underwent microdissection testicular sperm extraction. Patients were stratified by age 35 years or younger (n = 51) and older than 35 years (n = 21). Overall, germ cells were identified in 59.7% of cases, with no difference between patients 35 years or younger (58.8%) and older than 35 years (61.9%; P = .81). The overall SRR was 50%, with no difference by the age group (≤35 years: 51.0%, older than 35 years: 47.6%; P = .80). On multivariable analysis, age older than 35 years (odds ratio [OR] 0.82, 95% CI [0.28-2.40]) and the presence of spermatogenesis during biopsy (OR 1.66, 95% CI [0.59-4.69]) were not associated with SRR. Follicle-stimulating hormone levels between 12.4 and 24.0 mIU/mL were associated with higher SRR (OR 7.04, 95% CI [1.83-27.1]). Patient age was not a strong predictor of sperm retrieval success in men with complete AZFc deletion. Follicle-stimulating hormone levels within an intermediate range were associated with higher SRRs, suggesting that hormonal context may inform patient counseling. Reproductive urologists should counsel patients that age alone is unlikely to meaningfully influence sperm retrieval.

The detection of Y chromosome microdeletions (YCMDs) in the azoospermia factor (AZF) region is a critical diagnostic tool for male infertility. The present study aimed to determine the prevalence of YCMDs among Libyan men with infertility following the European Academy of Andrology (EAA) and the European Molecular Genetics Quality Network (EMQN) guidelines. The present descriptive cross-sectional study included 41 men with infertility, stratified into two primary groups for comparative analysis: One group with azoospermia (n=23) and a non-azoospermia group (n=18). Genetic screening for AZFa, AZFb and AZFc microdeletions was performed using multiplex PCR with standardized sequence-tagged site primers (sY84, sY127, sY254, sY86, sY134 and sY255). Hormonal profiles, including follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and prolactin (PRL), as well as their ratios, were evaluated. The overall prevalence of YCMDs was 2.44% (1/41; 95% confidence interval, 0.06-12.79%). A single case of a complete AZFb+c microdeletion was identified in a patient with azoospermia. The azoospermia group exhibited significantly higher mean FSH (P<0.001) and LH levels (P<0.01) than those of the non-azoospermia group. The azoospermia group demonstrated a suppressed LH/FSH ratio (0.61) and a reduced T/LH ratio (0.37), indicating testicular failure and compensated Leydig cell dysfunction, respectively. To the best of our knowledge, the present study represents the first investigation in Tripoli, Libya, to report the prevalence of YCMDs in accordance with the EAA/EMQN international standards. Future large-scale, multicenter studies incorporating larger cohorts, fertile control groups, and broader geographic representations, are essential to establish a comprehensive genetic landscape of male infertility in Libya.

Infertility affects approximately 10% to 15% of couples attempting to conceive, with a male factor contributing to nearly half of these cases. The most common molecular abnormality associated with male infertility is Y-chromosome microdeletion (YCM), which involves deletions in the azoospermia factor (AZF) regions-gene clusters essential for spermatogenesis. This study aimed to determine the prevalence of YCM among infertile Moroccan men and to assess the effectiveness of multiplex ligation-dependent probe amplification (MLPA) for Y-chromosome analysis in this context. A cohort of 41 infertile Moroccan men diagnosed with either severe oligozoospermia (n=16) or azoospermia (n=25) underwent comprehensive clinical, paraclinical, and molecular analysis of the AZF regions using the MLPA technique. An additional 20 normozoospermic men were included as control subjects. AZFc microdeletions and duplications were identified in 12% and 7% of patients, respectively. No deletions were detected in the AZFa or AZFb regions, nor in the control group. The overall prevalence of YCM in this cohort is consistent with that reported in other Moroccan studies. However, to our knowledge, the complete copy number variation (CNV) profile of the Y-chromosome-including duplications-has not been previously investigated in the Moroccan population. This study identified a 19% prevalence of CNVs restricted to the AZFc region among infertile Moroccan men, underscoring its specific association with severe spermatogenic failure. MLPA demonstrated high accuracy, reproducibility, and cost-effectiveness for CNV detection. These findings support the implementation of MLPA as a routine genetic diagnostic and counseling tool for men with significant sperm abnormalities.

Sex-specific marker abnormalities in a phenotypic male involved in a sexual assault case.

Infertility affects approximately 50 million couples worldwide, with both men and women being equally affected. Male infertility is a complex issue with genetic factors playing a significant role. Conditions such as Klinefelter syndrome (XXY), Y chromosome microdeletions (YCMDs), and monogenic mutations can contribute to male infertility. Currently, hereditary factors account for 4% of male infertility cases, while the causes of 60-70% of cases remain unknown. Ongoing research aims to identify new genes and variants related to male fertility to improve diagnostic methods. More than 2000 genes are believed to be involved in preserving germ cells and ensuring normal meiosis, with more than 100 genes already identified for male infertility. In this case series study, we assessed a patient with unexplained male infertility, who also had a brother with a similar issue. We used whole exome sequencing (WES) technology, segregation analysis and analyzed the data through bioinformatics tools. Bioinformatics analysis and Sanger sequencing revealed that two infertile brothers had a compound heterozygous (CH) mutation with missense variants in dynein axonemal heavy chain 5 (DNAH5) gene: one variant in exon 9, (c.1121T>C: p.Ile374Thr), and another in exon 66, (c.11437C>T: p.Arg3813Trp). The protein structure analysis showed that the Ile374Thr variant is located near the outer dynein arm-docking subunit 1 (ODA-D1) and ODA-D3. Additionally, the Arg3813Trp variant replaces the positively charged arginine with a hydrophobic tryptophan residue, which may lead to local instability in the protein structure, particularly in the ATP-binding site. Our study reports a CH presence of a missense variant in DNAH5 within a family experiencing male infertility. In silico structural predictions suggest a potential role of these DNAH5 variants in causing fertility issues.

Male infertility is a significant reproductive health concern, with genetic abnormalities such as chromosomal aberrations and Y-chromosome microdeletions contributing substantially to severe spermatogenic failure. This cross-sectional study evaluated the prevalence and spectrum of chromosomal abnormalities and Y-chromosome microdeletions in infertile males from Eastern Uttar Pradesh using conventional karyotyping and quantitative fluorescence polymerase chain reaction (QF-PCR). A total of 134 infertile males were enrolled. Semen analysis was performed according to the World Health Organization (WHO) 6th edition guidelines. Peripheral blood samples were subjected to karyotyping, followed by Y-chromosome microdeletion analysis using QF-PCR in individuals with normal karyotypes. Chromosomal abnormalities were identified in 23.1% of cases, with mosaic karyotypes accounting for approximately 18% of the total cohort. Mosaic Klinefelter syndrome (46,XY/47,XXY) was the predominant abnormality, observed in 14.2% of cases. Among men with normal karyotypes (n = 103), Y-chromosome microdeletions were detected in 29% using the AZF v2 kit, mainly involving the AZFb and AZFc regions. Extended STS marker analysis further identified additional deletions in 31% of initially negative cases, including partial AZFc and AZFa-associated deletions, thereby significantly improving the overall diagnostic yield. These findings highlight the importance of a combined cytogenetic and molecular approach for the genetic evaluation of male infertility. While karyotyping remains essential for detecting large chromosomal abnormalities, extended STS-based molecular screening enhances diagnostic yield, particularly in resource-limited clinical settings.

BACKGROUND. Male infertility is a significant medical and social problem affecting approximately 7% of the male population worldwide. Genetic factors play a key role in the pathogenesis of spermatogenesis disorders, especially in azoospermia and severe oligozoospermia, but diagnostic and therapeutic approaches require constant updating in accordance with modern advances in molecular genetics. OBJECTIVE. To systematize current data on genetic causes of male infertility, diagnostic testing algorithms, and personalized therapeutic strategies for patients with various genetic variants of infertility. MATERIALS AND METHODS. Analysis of scientific literature on genetic aspects of male infertility was performed, including chromosomal abnormalities, molecular genetic defects, diagnostic methods, and modern treatment approaches using assisted reproductive technologies. RESULTS. The article presents a detailed classification of genetic causes of male infertility, including Klinefelter syndrome (detected in 10–15% of patients with non-obstructive azoospermia), Y-chromosome microdeletions (5–10% of cases of idiopathic azoospermia), monogenic diseases (cystic fibrosis, Kallmann syndrome, primary ciliary dyskinesia), and polygenic forms. Indications for various types of genetic testing depending on clinical manifestations are considered. Personalized therapeutic strategies for each nosological form are presented with emphasis on the use of microdissection testicular sperm extraction (micro-TESE), intracytoplasmic sperm injection (ICSI), and preimplantation genetic testing. It is shown that the success rate of sperm retrieval varies from &lt;5% in AZFa deletions to 50–70% in AZFc deletions, while in hypogonadotropic hypogonadism, spermatogenesis induction is possible with success rates up to 90%. CONCLUSIONS. Genetically determined male infertility requires a multidisciplinary approach with mandatory genetic testing, personalized selection of therapeutic strategy, and comprehensive genetic counseling of couples. Preimplantation testing plays a critical role in preventing transmission of genetic abnormalities to offspring. Further development of genome editing technologies and in vitro spermatogenesis promises new opportunities for patients with genetically determined infertility.

P0415 Missed karyotype abnormalities and Y-chromosome microdeletions in male infertility: Trial simulation challenges current European Association of Urology guidelines genetic testing thresholds

Aim: to compare international and Russian epidemiological data on the causes of oligozoospermia and to develop differential diagnostics and patient management algorithm by taking into account endocrine, genetic and immunological factors. Materials and Methods. A retrospective observational study included 210 men aged 25-45 years with confirmed oligozoospermia and infertility complaints. All patients underwent semen analysis according to the World Health Organization standards (2021), blood hormone testing (follicle-stimulating hormone, luteinizing hormone, total testosterone, prolactin, thyroid-stimulating hormone, estradiol, inhibin B, anti-Müllerian hormone, 17-hydroxyprogesterone), scrotal ultrasound, as well as genetic testing (karyotyping and Y-chromosome microdeletions). The data provided by international clinical guidelines, European Association of Urology (EAU, 2024), American Urological Association/American Society for Reproductive Medicine (AUA/ASRM, 2024), publications in Russian and English retrieved from PubMed/MEDLINE, Scopus and eLibrary databases were analyzed. Results. A wide spectrum of oligozoospermia causes was identified: endocrine disorders (hypo- and hypergonadotropic hypogonadism), Klinefelter syndrome, Y-chromosome microdeletions, varicocele, and obstructive forms. The pathophysiological mechanisms of hypogonadism, the clinical significance of Klinefelter syndrome, features of Y-chromosome azoospermia factor deletions, and the role of varicocele as a potentially reversible cause of male infertility are discussed in detail. Conclusion. Differential diagnosis of oligozoospermia requires a comprehensive, stepwise approach. Incorporating repeated semen analysis, hormonal profiling, ultrasound, and genetic testing into the diagnostic algorithm enables identification of reversible causes (varicocele, hypogonadotropic hypogonadism) as well as timely diagnostics of genetic forms (Klinefelter syndrome, Y-chromosome microdeletions). This ensures a personalized therapeutic strategy and improves the effectiveness of assisted reproductive technologies.

Male infertility accounts for approximately 30–50% of infertility cases worldwide and poses a significant reproductive health challenge. This review synthesizes current knowledge on the etiology of male infertility, emphasizing the pivotal role of diagnostic imaging, particularly ultrasonography, in identifying structural and functional abnormalities. Common causes include varicocele, testicular failure, genetic abnormalities such as chromosomal defects and Y-chromosome microdeletions, obstructive pathologies, and idiopathic factors. Ultrasound techniques, especially scrotal and transrectal ultrasonography, have become essential tools in detecting conditions often missed during routine examinations, thereby facilitating accurate diagnosis and targeted management. Despite advancements, standardization of imaging protocols and access remain limited in resource-constrained settings. An integrated diagnostic approach, combining semen analysis, hormonal profiling, genetic testing, and imaging, enhances diagnostic precision, reduces unexplained cases, and guides personalized treatment. Early identification of causative factors is crucial for optimizing reproductive outcomes.

ObjectiveTo analyze the incidence of different types of Y chromosome microdeletions in infertile male patients in China, and to investigate the relationship between microdeletions in different azoospermia factor (AZF) regions and sperm kinetic parameters, sperm morphological parameters, and sex hormone levels.MethodsA total of 2010 infertile male patients who visited the Fujian Provincial Maternity and Child Health Hospital from 2022 to 2025 were selected. Their Y chromosome microdeletions (YCMD), semen routine, sperm morphology, sperm DNA fragmentation index (DFI), and sex hormone levels were detected, and the relationships between these parameters were analyzed.ResultsThe incidence of Y chromosome microdeletions in patients was 8.66% (174/2010). Among the 174 patients with AZF microdeletions, the proportion of AZFc region deletions was 85.63% (149/174), AZFa region deletions accounted for 2.30% (4/174), AZFb/c region deletions accounted for 8.05% (14/174), AZFa/b/c region deletions accounted for 2.87% (5/174), and heterochromosome deletions accounted for 1.15% (2/174). There were no statistically significant differences in semen volume, testosterone (T), and prolactin (PRL) levels between patients with different types of AZF deletions and the normal group (P>0.05). There were statistically significant differences in sperm concentration, progressive motility (PR), non-progressive motility (NP), total sperm motility, normal sperm morphology rate, sperm DFI, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) between patients with different types of AZF deletions and the normal group (P<0.05).ConclusionAZFc deletion is the most common type of Y chromosome microdeletion in infertile male patients in China. Patients with AZFa and AZFa/b/c combined deletions often present with azoospermia. AZFc deletion is associated with abnormal sperm quality parameters and disordered hormone levels.

In recent years, male infertility has shown a significant upward trend globally. Y chromosome microdeletions (YCMs), known as microdeletions within azoospermia factor (AZF), and chromosomal abnormalities are the leading genetic causes of male infertility. This study summarizes the detection of YCMs, karyotype results, and sex hormone levels in male infertility patients, with the aim of providing theoretical support for clinical diagnosis and treatment. A retrospective analysis was conducted on 3060 male infertility patients treated at the General Hospital of Ningxia Medical University between January 2016 and December 2024. Patients were classified according to semen parameters into azoospermia and oligozoospermia groups, and subgroup analyses were performed to compare the prevalence of YCMs and karyotypic abnormalities, as well as to assess hormonal differences between groups. The overall detection rate of YCMs in patients with infertility was 8.24%. AZFc deletions were most common (64.68%), followed by AZFb + c deletions (19.05%). YCMs were significantly more prevalent in azoospermia (12.70%) than in oligozoospermia (5.99%) (P < .001). AZFb + c deletions predominated in azoospermia (36.92%), whereas AZFc deletions were nearly exclusive in oligozoospermia (98.36%). The overall chromosomal karyotype abnormality rate was 8.01%, which was significantly higher in the azoospermia (15.72%) group than in the oligozoospermia (4.13%) group (P < .001). Patients with YCMs exhibited a significantly higher rate of abnormal karyotypes (40.48%) than those without YCMs (5.09%) (P < .001). Azoospermia patients had significantly higher luteinizing hormone and follicle-stimulating hormone levels and lower testosterone levels than oligozoospermia patients (all P < .001). Patients with YCMs had significantly higher luteinizing hormone and follicle-stimulating hormone levels than those without YCMs (P < .001 and P < .05) and the hormonal alterations associated with YCMs were independent of age. Genetic screening is conducive to identifying potential genetic disorders that may be associated with infertility, providing auxiliary support for the formulation of personalized treatment plans and the selection of appropriate assisted reproductive technologies.

(143) Bridging Genetics and Management: Hormonal Insights From Men With Azoospermic Factor(AZF) Microdeletions

Non-obstructive azoospermia (NOA) is one of the most severe manifestations of male infertility, accounting for up to 70% of azoospermic cases and affecting approximately 1% of the male population. Advances in genomics and epigenetics have transformed our understanding of NOA from a primarily idiopathic condition into a biologically heterogeneous disorder driven by diverse molecular mechanisms. This review synthesizes the current knowledge of the genetic and epigenetic landscape of NOA, integrating chromosomal abnormalities, single-gene mutations, and non-coding RNA (ncRNA) dysregulation. First, we systematically examine classical and emerging chromosomal defects-including karyotype anomalies, Y-chromosome microdeletions, and structural rearrangements-that disrupt meiotic pairing and chromatin organization. Next, we explore syndromic and non-syndromic monogenic mutations affecting meiotic regulators, DNA repair factors, transcription regulators, and chromatin remodelers. Particular emphasis is placed on recently identified genes such as SYCP1, SYCE1 and HORMAD1, whose pathogenic variants are frequently linked to spermatogenic arrest. We then discuss the expanding role of ncRNAs-including microRNAs, PIWI-interacting RNAs, long non-coding RNAs, and circular RNAs-in regulating germ cell apoptosis, transposon silencing, and epigenetic reprogramming. Furthermore, we highlight the translational potential of these molecular insights (including gene variants, ncRNAs and protein) in clinical applications. Genotype-guided sperm retrieval, non-invasive biomarkers, and multi-omic approaches are discussed as promising tools to improve diagnosis and treatment. Moreover, we summarize current and emerging strategies for the treatment and fertility preservation of NOA. Finally, we identify persisting challenges, such as genotypic heterogeneity and incomplete functional validation, and emphasize the need to elucidate interactions between ncRNA and classical genetic pathways to uncover regulatory hierarchies underlying NOA. By integrating molecular genetics with testicular histopathology and clinical phenotypes, this review highlights emerging genetic and ncRNA biomarkers and underscores their potential applications in the clinical management of NOA. Ultimately, a comprehensive understanding of the genetic and epigenetic underpinnings of NOA will be essential for advancing precision diagnostics and improving reproductive outcomes in affected men.

What is the impact of undiagnosed microdeletion and microduplication syndromes (MMS) for men with idiopathic low sperm count? Among idiopathic male infertility, ∼2% of cases harbour known disease-causing microdeletions and duplications linked to clinically well-established syndromes, representing ∼2.5-fold higher prevalence than in the general population. While infertility affects up to 10% of men, a substantial proportion of cases remain with no identifiable underlying cause. Recurrent submicroscopic losses or gains cause MMS, some of which also impact reproductive phenotypes, including cryptorchidism and reduced fertility. This retrospective study investigated the proportion of undiagnosed MMS among idiopathic male infertility cases. Patients with unexplained low total sperm counts (TSC; defined as ≤39 million sperm per ejaculate) were recruited to the ESTonian ANDrology (ESTAND) cohort at the Andrology Clinic of Tartu University Hospital (AC-TUH) in Estonia. A total of 504 men were included in the analysis, and the study capitalized on available whole-exome sequencing (WES) data to explore large (>500 kb) chromosomal deletions and duplications. Copy number variant (CNV) calling was executed on the WES dataset, followed by a stringent, custom-developed filtering pipeline that retained only high-confidence CNVs larger than 500 kb. Candidate CNVs were validated by chromosomal microarray analysis (CMA) or whole-genome sequencing (WGS). Prevalence of identified MMS-linked deletions and duplications in the ESTAND cohort was compared to general population literature data. A total of nine patients (1.8%) carried losses and gains linked to clinically well-characterized MMS-recurrent microdeletions at 16p11.2 (two cases), 2q13-14.1, and 15q13.2-13.3, and microduplications at 22q11.21 (three cases), 16p11.2, and 8p23.1. The total burden of MMS among infertile men was ∼2.5-fold higher compared to the general population (P = 0.01, χ2 test). Cryptorchidism was a novel shared feature among all individuals with 16p11.2 rearrangements, suggesting a potential role in disrupting testicular development. Three subjects with MMS-linked microduplications, but none with a microdeletion, had achieved biological fatherhood. An oligozoospermia case (TSC 1.92 × 106/ej.) with 16p11.2 duplication had a naturally conceived child in youthhood. For two men carrying 22q11.21 duplication (TSC 0 and 4.2 × 106/ej., respectively), implementation of ARTs-ICSI with or without preceding testicular sperm aspiration-resulted in successful conception and childbirth. Evidence for a plausible link to male gonadal development and function has been reported for MAZ and KCTD13 at 16p11.2, and LZTR1 at 22q11.21. As an additional finding, a novel ∼3.8 Mb microduplication at 3p25.1 was identified in an oligozoospermia patient and his azoospermic son, conceived naturally at the age of 28 years. This region encompasses a triplosensitive gene, NR2C2, linked to affected meiosis and oligozoospermia in mouse models. WES may not detect all structural variations, such as inversions or balanced translocations. As some MMS CNVs were only identified in singleton cases (8p23.1 duplication, 2q13-14.1 and 15q13.2-13.3 deletions), the link to male infertility could not be clarified. Further data are needed about the novel large 3p25.1 microduplication to understand its effect on spermatogenesis. The yield of identified MMS in idiopathic cases with low sperm counts (∼2%) was close to the carriership of Y-chromosome microdeletions, tested in routine infertility workup. Early identification of MMS can inform genetic counselling regarding congenital health risks to the patient and future offspring and options for decision-making in ART. This study was supported by the Estonian Research Council (Grant number PRG1021 to M.L.). The authors declare that they have no conflict of interest in relation to the data in this paper. N/A.

Novel genetic variants of sperm chromatin compaction regulators are associated with non-obstructive azoospermia in Indian men.

Background: Infertility affects approximately one in seven couples worldwide and arises from a heterogeneous interplay of chromosomal abnormalities, monogenic defects, polygenic susceptibility, epigenetic dysregulation, mitochondrial dysfunction, and environmental factors, yet a large proportion of cases still lack a clearly defined genetic etiology. Objective: To synthesize current evidence on the genetic, epigenetic, and mitochondrial determinants of male and female infertility, and to examine how these discoveries inform diagnostic evaluation, clinical management, and ethical, legal, and social frameworks. Methods: A narrative review of the literature was conducted using searches of major biomedical databases and targeted snowballing to identify original research, reviews, and professional guidelines on chromosomal, monogenic, polygenic, epigenetic, and mitochondrial mechanisms in human infertility, as well as their clinical translation into genetic testing, preimplantation genetic testing, and counseling. Results: Sex-chromosome aneuploidies, Y-chromosome microdeletions, and an expanding set of monogenic defects explain substantial fractions of severe male factor infertility and primary ovarian insufficiency, while GWAS have revealed complex polygenic architectures for polycystic ovary syndrome and endometriosis. Epigenetic and mitochondrial perturbations influence gamete competence and ART outcomes, and genetic testing and preimplantation genetic testing are increasingly embedded in guidelines, though access, variant interpretation, and ethical concerns remain challenging. Conclusion: The genetic landscape of human infertility is broad and rapidly evolving; integrating chromosomal, monogenic, polygenic, epigenetic, and mitochondrial insights into personalized reproductive care requires continued gene discovery, multi-ancestry research, robust counseling, and ethically grounded policy.

Introduction . Azoospermia, defined as the absence of spermatozoa in the ejaculate after centrifugation, is one of the leading causes of male infertility, affecting approximately 1,0 % of men in the general population and up to 15,0 % of infertile patients. Timely differentiation between obstructive (ОА) and non-obstructive (NOA) azoospermia is critical for selecting appropriate treatment strategies, determining prognosis, and applying assisted reproductive technologies (ART). Aim : to investigate the prevalence of different azoospermia forms of azoospermia in infertile men, within the context of real-world clinical practice at a non-specialized endocrine outpatient department, including personal observations, with consideration of/in comparison with the results of international and Russian epidemiological studies. Materials and Methods . A comprehensive analysis of literature, clinical guidelines, and original data was performed. The study included 450 men aged 25–45 years with confirmed azoospermia. All patients underwent a comprehensive examination, including collection of anamnesis (reproductive, somatic, surgical); physical examination with assessment of secondary sexual characteristics, size and consistency of the testicles; double examination of ejaculate (centrifugation, microscopy); examination of blood hormone levels (follicle-stimulating hormone, luteinizing hormone, total testosterone, prolactin, anti-Müllerian hormone, sex hormone-binding globulin, inhibin B; if indicated – estradiol, thyroid-stimulating hormone, thyroxine); scrotum ultrasound examination with Doppler ultrasonography; genetic testing – karyotyping, testing for microdeletions of Y chromosome azoospermia factor ( AZF ) of the Y chromosome, CFTR (cystic fibrosis transmembrane conductance regulator) gene testing; when indicated, testicular sperm extraction (TESE) biopsy was performed. Results . NOA and OA were identified in 63.3 % and 30 % of patients, respectively. Among NOA cases, the leading causes were idiopathic forms (19.6 %), Klinefelter syndrome (8.4 %), Y-chromosome microdeletions (5.8 %), and hypogonadotropic hypogonadism (6.7 %). Varicocele was associated with NOA in 12 % of cases. These findings are consistent with global data, although minor ethnic and methodological differences were observed. Conclusion . Azoospermia is a clinically and etiologically heterogeneous condition. Timely differentiation between its forms and the inclusion of genetic testing improve diagnostic accuracy and help optimizing management strategies. Standardization of diagnostic algorithms and a personalized approach increase ART effectiveness and the likelihood of fertility restoration.

Approximately 7% of males globally suffer from male infertility, which is becoming more widely acknowledged as a clinical indicator of potential health hazards as well as a cause of reproductive failure. Among these, cancer has become a significant worry due to mounting evidence that spermatogenesis impairment is associated with increased risk of prostate, testicular, and other cancers. Male infertility may be an early clinical manifestation of systemic genomic instability due to shared biological pathways, such as Y-chromosome microdeletions (AZF regions), germline DNA repair defects, mutations in tumor suppressor genes (e.g., BRCA1/2, TP53), mismatch repair gene mutations (e.g., MLH1, MSH2), and dysregulated epigenetic profiles. This narrative review covers the most recent research on prognostic markers of cancer in infertile men. These include molecular biomarkers such as genetic, epigenetic, and proteomic signatures; endocrine and hormonal profiles; and clinical predictors such as azoospermia, severe oligozoospermia, and a history of cryptorchidism. The possibility of incorporating these indicators into risk stratification models for precision medicine and early cancer surveillance is highlighted. For this high-risk group, bridging the domains of andrology and oncology may allow for better counseling, earlier detection, and focused therapies.

Male infertility in Pakistan exhibits unique genetic patterns due to high consanguinity rates (65%). This systematic review of 38 studies (2015-2025) analyzed 2,041 participants (1,503 infertile men, 538 controls) using whole-exome sequencing (WES). Key findings reveal distinct genetic causes and inheritance patterns specific to this population. Chromosomal abnormalities affected 20.9% of azoospermic men, primarily Klinefelter syndrome (14.7%). Y-chromosome microdeletions occurred in 8% of cases, mostly in the AZFc region (50%). We identified 72 pathogenic variants across 58 genes, with 70.8% being novel to Pakistani populations. Consanguinity drove homozygous inheritance in 72.2% of cases. The most frequently mutated genes included ADAD2 (30% of non-obstructive azoospermia), HFM1 (20%), and DNAH family members (28.7% of motility defects). Variant types comprised frameshift (38.9%), missense (33.3%), nonsense (16.7%), and splicing mutations (11.1%). Significant biochemical markers included the CAT rs7943316 TT genotype (70.9% vs 14% controls) and elevated oxidative stress markers. These findings establish the first comprehensive genetic profile of Pakistani male infertility, demonstrating the profound impact of consanguinity on disease expression. The results emphasize the need for population-specific diagnostic protocols that prioritize DNAH/CFAP genes for motility disorders and ADAD2 for non-obstructive azoospermia. This review provides critical insights for genetic counseling and clinical management in high-consanguinity populations.