RARE DISEASE
Chromosome Y microdeletion
Chromosome Y microdeletion
Chromosome Y microdeletion
Synonyms: Male infertility due to chromosome Y microdeletion, Microdeletion of the AZF region on the Y chromosome
Synonyms: Male infertility due to chromosome Y microdeletion, Microdeletion of the AZF region on the Y chromosome
Synonyms: Male infertility due to chromosome Y microdeletion, Microdeletion of the AZF region on the Y chromosome
Drug discovery
108
papers
On emerging therapies
Overview
Chromosome Y microdeletion syndrome involves deletions in AZF regions (azoospermia factor a, b, or c) on the Y chromosome long arm, causing spermatogenic failure leading to azoospermia (absent sperm) or severe oligozoospermia (<1 million sperm/mL) [1][4][6]. These deletions are found in 5-15% of men with non-obstructive azoospermia and 3-7% with severe oligozoospermia [1][6][17]. AZFc deletions (70% of cases) may allow sperm retrieval via testicular extraction for ICSI, while AZFa/b deletions often preclude biological parenthood [1][3][4].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare infertility disorders
Research Papers
108 drug discovery papers about Chromosome Y microdeletion. Recent publications:
108 drug discovery papers about Chromosome Y microdeletion. Recent publications:
categories:
Small molecules
gene therapies
2026-03-30 | GENETIC ASPECTS OF MALE INFERTILITY: MODERN APPROACHES TO DIAGNOSIS AND TREATMENT
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 <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.
2026-02-25 | Comparative analysis of data of comprehensive genetic and semen examination in patients with sex chromosomes abnormalities
Background. Sex chromosome abnormalities (gonosomes) are one of the common genetic causes of male infertility associated with impaired sex formation, developmental abnormalities, hypogonadism, spermatogenesis disorder, non-obstructive azoospermia and oligozoospermia. The presence and severity of spermatogenesis defects and meiosis, semen parameters in patients with various mutations of sex chromosomes may vary depending on the form of genotype, however, the mechanisms and pathogenesis, geno-phenotypic correlations, and clinical variability of many forms of genetic forms of male infertility have not been sufficiently studied. The aim of the work was the comparative analysis of spermatological parameters and genetics changes of the sex chromosomes in patients with various sex chromosomes abnormalities. Materials and Methods. A cohort of 261 men with disorders of sexual development (DSD) and/or sex chromosome abnormalities (Klinefelter syndrome, n=108; Y dysomy, n=20; patients with structural abnormalities of the Y chromosome and/or mosaicism on the Y chromosome, n=99; 46,XX-testicular DSD, n=34) was studied. A comprehensive spermatological (standard semen analysis, quantitative karyological analysis of immature germ cells from ejaculate sediment) and genetic (chromosome analysis, molecular cytogenetic and molecular genetic) examination was performed. Results. Spermatological diagnoses with spermatogenesis disorder were detected in 97% of the patients in the sample, including azoospermia and cryptozoospermia (71%). These forms of pathozoospermia were noted in all men with 46,XX DSD, in 83% of men with Klinefelter syndrome, in 62% of men with unbalanced structural abnormalities and/or mosaicism on the Y chromosome, and in 45% of men with Y dysomy. For patients examined with the quantitative karyological analysis of immature germ cells from ejaculate sediment, features of partial block of spermatogenesis at the stage of prophase I of meiosis were revealed. The total number of sperm in the ejaculate in the group with Klinefelter syndrome (0.39± 2.38 (0.00-25.0) million) is significantly lower than in men with dysomy Y (47.15± 77.17 (0.00-265.00) million) and with mosaicism/structural abnormalities Y (8.93 ± 31.72 (0.00-185.00) million). However, it did not significantly differ from patients with 46,XX DSD (0.03 ± 0.08 (0.00-0.375) million). Differences in the frequency of azoospermia were found between groups of patients with Klinefelter syndrome and dysomy Y in karyotype, with Klinefelter syndrome and mosaicism/structural abnormalities of Y, with dysomy Y and with 46,XX DSD. Ejaculate volume parameters significantly differed between patients with mosaics/structural abnormalities (3.6 ± 1.6 (0.2-8.2) ml) and those with 46,XX DSD (2.3 ± 1.4 (0.1-5.1) ml). Conclusion. 90% of patients with sex chromosome DSD and/or unbalanced sex chromosome abnormalities are characterized by primary male infertility caused by severe defects of spermatogenesis, leading to severe nonobstructive azoospermia and oligozoospermia. The most severe spermatogenesis disorders were noted in patients with Klinefelter syndrome, 46,XX testicular DSD and infertile men with unbalanced structural abnormalities of the Y chromosome with extended Y chromosome microdeletions (AZFb+c, AZFb), as well as in patients with structural abnormalities that disrupt the meiotic recombination of sex chromosomes (ring and dicentric Y chromosomes). Less manifested spermatological disorders were noted in the group of patients with Y dysomy, as well as Y-chromosome mosaics and carriers of Y structural abnormalities without deletions at the AZF locus.
2026-02-03 | Multiparametric descriptive and comparative analyses between fertile versus infertile men with severe oligozoospermia and azoospermia
Male infertility represents a major global health concern, often associated with conditions such as severe oligoasthenoteratozoospermia and azoospermia. The aim of the study was to compare clinical, biochemical, and genetic characteristics between infertile men and fertile controls. A prospective case-control study was conducted involving 180 participants, including 90 infertile men (45 with severe oligoasthenoteratozoospermia and 45 with azoospermia) and 90 fertile controls. Semen analysis, testicular ultrasound, vitamin D levels, and genetic testing.were performed. In men with severe oligoasthenoteratozoospermia, significantly reduced mean values were observed for sperm concentration (1.77±2 million/mL), total sperm count (5.59±8 million), total motility (12.64±16%), progressive motility (7.93±12%), vitality (13.64±18%), and normal morphology (1.02±2%) compared to controls. Vitamin D levels were slightly higher in the study group (29.37±9.3 ng/mL) than in controls (25.38±10.2 ng/mL). Average testicular volumes were 12.50±5.47 mL (right) and 12.30±5.09 mL (left). Abnormal echotexture and echogenicity were noted in 24.6% and 31.5% of right testes and 15.6% and 25.5% of left testes, respectively. Y chromosome microdeletions (sY242, sY1291, sY255, sY254) were identified in 4.4% of cases. An abnormal karyotype was found in 7.8% of infertile participants, while 92.2% had a normal karyotype. Compared with fertile men, severe oligoasthenozoospermia and azoospermia show marked alterations in semen, testicular, genetic, and endocrine parameters.
2025-12-17 | Unraveling the human Y chromosome in male health: structural abnormalities and microdeletions with emerging clinical implications
Abstract The human Y chromosome has traditionally been viewed as a gene-poor chromosome, primarily relevant to male reproductive health. However, recent evidence challenges this narrow perspective. This narrative review explores the Y chromosome’s unique structure, evolution, and functional relevance, with a particular focus on the azoospermia factor (AZF) regions and their associated genes. We examine how microdeletions in these regions, along with Y chromosome abnormalities, contribute to male infertility and discuss the underlying genetic mechanisms. Beyond reproduction, emerging evidence connects Y-linked variation and loss of Y (LOY) to cardiometabolic disorders and cancer. In addition, we highlight the importance of current diagnostic techniques used to detect Y chromosome abnormalities, including molecular and cytogenetic methods for infertility diagnosis. Understanding the Y chromosome’s genetic landscape is essential not only for accurate diagnosis but also for advancing precision medicine, forensic genetics, and potential gene-based interventions.
2025-11-30 | The Genetic Landscape of Human Infertility: A Comprehensive Review
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.
small molecules
2026-09-23 | DDX3Y Loss-of-Function Variant in AZFa-Like Non-Obstructive Azoospermia Highlights Gaps in Current Y-Chromosome Microdeletion Testing.
Some men have no sperm in the semen because sperm production in the testis has failed. In selected patients, surgical sperm retrieval may be performed, in which small pieces of testicular tissue are examined to look for rare sperm that could be used for intracytoplasmic sperm injection, a form of IVF in which a single sperm is injected into an egg. Before surgery, men are usually tested for large missing regions on the Y chromosome, including the AZFa region. Complete AZFa deletions are associated with a very poor chance of finding sperm. In this case report, we describe a man with no sperm in the semen, negative standard AZF deletion testing, and no sperm found during microdissection testicular sperm extraction. Later exome sequencing identified a previously unreported stop-gain variant in DDX3Y, a gene located within AZFa and now considered to have moderate evidence for involvement in severe sperm-production failure. Together with previously published cases, this finding illustrates a limitation of standard deletion testing: it cannot detect small gene-level variants. In carefully selected men with an AZFa-like clinical picture, DDX3Y sequence analysis may improve counseling and may help avoid low-yield surgery, but larger studies and economic evaluation are needed.
2026-03-19 | Idiopathic male infertility revisited: can redox endophenotypes reframe the 'idiopathic' label?
Male infertility accounts for nearly half of all infertility cases worldwide, yet up to 30-40% of affected men remain categorized as 'idiopathic', reflecting limitations of conventional diagnostics such as semen analysis, hormonal profiling, karyotyping, and Y-chromosome microdeletion testing. These methods describe sperm quantity and morphology but fail to uncover underlying molecular dysfunctions. Increasing evidence suggests that oxidative stress plays a central role in driving sperm damage, encompassing lipid peroxidation, protein oxidation, mitochondrial dysfunction, DNA fragmentation, and epigenetic instability. Such diverse pathways highlight the inadequacy of a single idiopathic category and necessitate mechanistic stratification. This evidence-based study proposes redox endophenotypes, including hyper- and hypo-oxidative, DNA damage-dominant, mitochondrial dysfunction, epigenetic-redox, and inflammatory-redox phenotypes, as a framework for reclassifying idiopathic male infertility. Each phenotype integrates specific biomarkers, such as oxidation-reduction potential (ORP), isoprostanes, 8-hydroxy-2'-deoxyguanosine, or advanced oxidation protein products, with distinct functional impairments and clinical outcomes. Redox endophenotyping offers diagnostic refinement, guides personalized antioxidant or adjunctive therapy, and informs clinicians and embryologists for appropriate assisted reproductive technology (ART) protocols by counselling and treating the patient, and tailoring sperm selection and preparation strategies. Future directions include multi-center validation of redox assays, integration with omics and exposome data, and application of artificial intelligence for biomarker-driven algorithms. Recognizing redox endophenotypes not only reduces the reliance on exclusionary 'idiopathic' diagnoses but also advances precision andrology, improving patient diagnostics and care, reproductive outcomes and mitigating intergenerational health risks.
2025-11-01 | (143) Bridging Genetics and Management: Hormonal Insights From Men With Azoospermic Factor(AZF) Microdeletions
Abstract Introduction Male-factor infertility contributes to a substantial portion of infertility cases. Genetic factors are believed to play an important role, with Y chromosome microdeletions commonly identified among men with azoospermia. Due to the relatively high prevalence of these deletions, genetic testing for Y chromosome microdeletions has become a routine component of the diagnostic workup for infertile men. While deletions in the AZF (Azoospermia Factor) region are known to impair spermatogenesis, the hormonal profile in this population remains poorly characterized. Hormonal evaluation plays a key role in guiding treatment decisions, including the use of empirical medical therapy (EMT). However, there is limited data on hormonal profiles and EMT usage in men with AZF deletions. Objective We aimed to characterize preoperative hormonal profiles and evaluate the use and outcomes of EMT in men with AZF microdeletions undergoing surgical sperm retrieval. Methods We conducted a multi-institutional retrospective cohort study of men with genetically confirmed AZF micro-deletions, including AZFa, AZFb, AZFc, and combined deletions. Data were collected on preoperative serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), total testosterone (TT), and semen analysis parameters. Additionally, we evaluated patterns of empirical medical therapy (EMT) prescriptions and outcomes of surgical sperm retrieval. Results 40 men with confirmed Y-chromosomal micro-deletions across three academic centers was identified. Patients with SRY translocations (n=4) were excluded from the study. The final cohort included 27 patients with AZFc deletions (75%), 2 with AZFa (6%), 1 with AZFb (3%), and 6 with multilocus deletions (17%). FSH (reference: >7.6 mIU/mL) was elevated in 23 patients (64%), with a median of 19.6 IU/L (IQR: 14.4–25.8). LH (reference: >9 mIU/mL) was elevated in 8 patients (22%), with a median of 14.9 IU/L (IQR: 13.7–20.1). Overall median TT was 243.5 (7.7-379.7). TT was below the lower limit of normal (<300 ng/dL) in 13 patients (36%), with a median of 184 ng/dL (IQR: 133–233). Most patients were azoospermic on semen analysis (86%, n=31/36). Of the seven men treated with EMT, the majority (6/7, 86%) received clomiphene citrate. While there were differences in initial levels of TT, FSH, and LH for those treated with EMT compared to those without EMT, these were not statistically significant (Table 1). Among the 13 patients who underwent surgical sperm retrieval, 6 (46%) had successful outcomes; however, only one had received EMT. Conclusions Men with AZF deletions exhibit varying degrees of hormonal imbalance and rates of empirical medical therapy (EMT) use. Despite EMT, sperm retrieval outcomes were poor, with only 1 out of 7 EMT-treated patients achieving successful sperm retrieval. While hormonal differences were observed between those who received EMT and those who did not, these differences did not reach statistical significance. This is likely due to the limited sample size inherent to this rare patient population. Our findings underscore the variability in hormonal profiles and the unclear efficacy of EMT in promoting spermatogenesis in men with AZF deletions, highlighting the need for further research to inform standardized management strategies. Disclosure No
2024-04-09 | An update on non-obstructive azoospermia; a narrative review
Azoospermia could be either non-obstructive azoospermia (NOA) or obstructive azoospermia (OA). Clinical assessment (testis consistency & volume), laboratory testing (FSH), and genetic testing (karyotype, Y chromosome microdeletion, or specific genetic testing for hypogonadotropic hypogonadism) are used to distinguish NOA (which includes primary and secondary testicular failure) from OA. The treatment of NOA is still empirical. For hypogonadotropic hypogonadism, gonadotropin therapy is the only particular indication that consistently improves semen analysis and rates of conception. The typical treatment consists of gonadotropins (hCG and rFSH) combined, with GnRH therapy maintained for non-responders. Although there is a paucity of level I clinical data, drug therapy combining aromatase inhibitors and gonadotropins may be able to improve outcomes for men who need surgical sperm retrieval. Many trials have been tried for treating NOA, although none of these trials has consistently shown efficacy. This review offers a current overview of the causes, treatments, and management of non-obstructive azoospermia.
2020-11-25 | Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells.
Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA pathogenesis and normal spermatogenic microenvironment. Here, we profile >80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. We show that Sertoli cells, which form the scaffold in the testicular microenvironment, are severely damaged in NOA patients and identify the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature, but exhibit abnormal immune responses, while the cells in idiopathic NOA (iNOA) are physiologically immature. Furthermore, we find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.
proteins
2024-03-04 | A cryptozoospermic infertile male with Y chromosome AZFc microdeletion and low FSH levels due to a simultaneous polymorphism in the FSHB gene: a case report.
Genetic causes account for 10-15% of male factor infertility, making the genetic investigation an essential and useful tool, mainly in azoospermic and severely oligozoospermic men. In these patients, the most frequent findings are chromosomal abnormalities and Y chromosome long arm microdeletions, which cause a primary severe spermatogenic impairment with classically increased levels of FSH. On the other hand, polymorphisms in the FSH receptor (FSHR) and FSH beta chain (FSHB) genes have been associated with different FSH plasma levels, due to variations in the receptor sensitivity (FSHR) or in the production of FSH from the pituitary gland (FSHB). Here, we describe an unusual patient with a combined genetic alteration (classic AZFc deletion of the Y chromosome and TT homozygosity for the -211G>T polymorphism in the FSHB gene (rs10835638)), presenting with cryptozoospermia, severe hypospermatogenesis, and normal LH and testosterone plasma concentrations, but low FSH levels. The patient partially benefitted from treatment with FSH (150 IU three times/week for 6 months) which allowed him to cryopreserve enough motile spermatozoa to be used for intracytoplasmic sperm injection. According to our knowledge, this is the first report of an infertile man with AZFc microdeletion with low FSH plasma concentrations related to homozygosity for the -211G>T polymorphism in the FSHB gene.
2004-08-17 | Gonadotropin treatment of an azoospermic patient with a Y-chromosome microdeletion.
To report on the treatment with recombinant FSH of an azoospermic normogonadotropic patient with a Y-chromosome microdeletion. Case report. An assisted reproduction center. A 32-year-old patient with azoospermia. Histological testicular biopsy, Y-chromosome screening, FSH treatment, and intracytoplasmic sperm injection. Fertilization, embryo development, pregnancy, and delivery. After 6 months of treatment with gonadotropins, a small number of spermatozoa were found in the patient's ejaculate and used for IVF, resulting in a successful twin pregnancy and the delivery of two healthy girls. In this study, treatment with gonadotropins promoted the spermatogenesis process and led to the production of spermatozoa in a normogonadotropic azoospermic patient.
cell therapies
2026-07-29 | Live Birth Following Microdissection Testicular Sperm Extraction and Intracytoplasmic Sperm Injection: A Case Study of a Patient with Non-Obstructive Azoospermia and a Y-chromosome Microdeletion (Ym9; P3, Including AZFb, c Region).
The azoospermia factor (AZF) region on the long arm of the Y chromosome is instrumental in spermatogenesis. In particular, complete deletion of the AZFa, AZFb, and AZFb + c regions is not an indication for microdissection testicular sperm extraction (MD-TESE) as there is no chance of sperm retrieval. This report presents a rare case of a successful live birth, following intracytoplasmic sperm injection (ICSI) using sperm from a patient with a microdeletion of the Y chromosome, including part of the AZFb, c region, who underwent MD-TESE. A 3X-year-old Japanese man with azoospermia was admitted to our hospital in October X. Scrotal ultrasonography, physical examination, and genetic examination resulted in a diagnosis of non-obstructive azoospermia with Y chromosomal microdeletion of Ym-9 P3 (deletion of sequence-tagged site markers [sY2990][sY1197][sy1191], including part of the AZFb region). Thus, ICSI resulted in a successful fertilization and the subsequent birth of a child, suggesting its potential application in the field of in vitro fertilization.
2025-05-28 | Ethnic Differences in Genetic and Epigenetic Factors Related to Male Infertility: A Narrative Review
Male infertility causes problems in 7% of worldwide men which creates major difficulties for reproductive health and family planning. A combination of genetic factors and epigenetic factors with environmental elements and lifestyle choices creates causes of this condition. The treatment options available through assisted reproductive technologies (ART) give hope to couples yet we still know only a few aspects of genetic and epigenetic influences related to male infertility. Studies regarding ethnic differences have demonstrated that infertility incidence rates together with biological causes show substantial variation between different cultural groups. The differences become visible through both genetic mutation frequencies along with alterations in epigenetic controls of reproductive functions. Male infertility suffers from genetic elements that comprise Y-chromosome microdeletions and gene mutations in addition to single nucleotide polymorphisms (SNPs). Fewer studies have been conducted on different ethnic groups because their occurrence rates between populations show significant differences. The development of sperm cells depends critically on epigenetic processes which include DNA methylation and histone modification mechanisms. The modifications affect spermatogenesis and result from genetic factors along with environmental conditions that include diet and lifestyle habits and toxic exposures where these variances differ among ethnic groups. The understanding of genetic and epigenetic variations across ethnic populations creates essential effects on diagnosing and treating male infertility. The use of ethnic-specific profiles for diagnostic and treatment selection enhances both accuracy rates and treatment success outcomes. The analysis of ethnic differences makes the possibility of developing targeted reproductive healthcare initiatives along with methods to decrease reproductive health inequality. The article investigates the ways that genetic along epigenetic variations between ethnic populations affect male infertility rates. This review brings together existing knowledge while demonstrating unmet needs to underline the need for ethnic perspectives in studies involving infertility. The research advances methods for developing better specific diagnoses and treatment options for male infertility worldwide.
2024-09-11 | Familial DMRT1-related non-obstructive azoospermia: a case report.
To report an exceptional case of male-to-male transmission of genetically based non-obstructive azoospermia (NOA) and varicocele through a naturally obtained pregnancy. A father and his son were both diagnosed with NOA after centrifugation and varicocele. The father has no other clinical concerns apart from infertility, detected after many attempts of having another child, but given his urological situation (bilateral varicocele and NOA) assisted reproductive techniques were discouraged. After genetic counseling, several genetic-chromosomal analyses were carried out in the son (karyotype, chromosome Y microdeletions, CFTR screening, NGS infertility panels, and finally array-CGH). After a series of inconclusive tests, array-CGH detected a deletion of 224-283 kb (del9p24.3) involving part of the KANK1 and DMRT1 genes, inherited from the father. Haploinsufficiency of DMRT1 was therefore considered the determining factor in the development of azoospermia in the family by a loss of function mechanism. The confirmation of father-to-son transmission of a deletion including DMRT1 represents an important point for clinicians dealing with male infertility, even when complete azoospermia is repetitively detected, and must be of hope for a relevant portion of men. Inclusion criteria for the access to assisted reproductive techniques may also be reconsidered and worthy of a greater number of clinical insights. Finally, since DMRT1 alterations have been associated with NOA and abnormal testicular development, but not specifically with varicocele, further studies are required to validate this issue, as varicocele may have played a crucial role in this case.
2021-12-03 | Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis.
Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.
2021-10-12 | Complex Y chromosome anomalies in an infertile male.
Y chromosome anomalies are closely associated with non-obstructive azoospermia (NOA), a major etiology in male infertility. Klinefelter syndrome (KS) and Y chromosome microdeletions are some of the well-identified genetic defects in this regard, while Y chromosome aneuploidies have been reported to be susceptive. We report the rare case of a patient presenting with three complex genetic defects: mosaic Y chromosome aneuploidy; loss of the heterochromatin region in the q arm of the Y chromosome (Yqh-); and azoospermia factor C subregion (AZFc) microdeletion. The patient reported he had been subfertile for five years. Semen analysis confirmed total azoospermia along with an unaffected hormonal profile for serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels. Since the microdeletion analysis of azoospermia factor (AZF) region revealed the presence of three microdeletions in the AZFc region, the patient was offered intracytoplasmic sperm injection (ICSI) upon the retrieval of sperm by testicular sperm extraction (TESE) as the best possible assisted reproductive treatment (ART) option. It was further suggested to carry out pre-implantation genetic screening (PGS) in order to facilitate the transfer of only female embryos, thus preventing the dissemination of Y chromosomal anomalies.
gene therapies
2026-03-30 | GENETIC ASPECTS OF MALE INFERTILITY: MODERN APPROACHES TO DIAGNOSIS AND TREATMENT
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 <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.
2026-02-25 | Comparative analysis of data of comprehensive genetic and semen examination in patients with sex chromosomes abnormalities
Background. Sex chromosome abnormalities (gonosomes) are one of the common genetic causes of male infertility associated with impaired sex formation, developmental abnormalities, hypogonadism, spermatogenesis disorder, non-obstructive azoospermia and oligozoospermia. The presence and severity of spermatogenesis defects and meiosis, semen parameters in patients with various mutations of sex chromosomes may vary depending on the form of genotype, however, the mechanisms and pathogenesis, geno-phenotypic correlations, and clinical variability of many forms of genetic forms of male infertility have not been sufficiently studied. The aim of the work was the comparative analysis of spermatological parameters and genetics changes of the sex chromosomes in patients with various sex chromosomes abnormalities. Materials and Methods. A cohort of 261 men with disorders of sexual development (DSD) and/or sex chromosome abnormalities (Klinefelter syndrome, n=108; Y dysomy, n=20; patients with structural abnormalities of the Y chromosome and/or mosaicism on the Y chromosome, n=99; 46,XX-testicular DSD, n=34) was studied. A comprehensive spermatological (standard semen analysis, quantitative karyological analysis of immature germ cells from ejaculate sediment) and genetic (chromosome analysis, molecular cytogenetic and molecular genetic) examination was performed. Results. Spermatological diagnoses with spermatogenesis disorder were detected in 97% of the patients in the sample, including azoospermia and cryptozoospermia (71%). These forms of pathozoospermia were noted in all men with 46,XX DSD, in 83% of men with Klinefelter syndrome, in 62% of men with unbalanced structural abnormalities and/or mosaicism on the Y chromosome, and in 45% of men with Y dysomy. For patients examined with the quantitative karyological analysis of immature germ cells from ejaculate sediment, features of partial block of spermatogenesis at the stage of prophase I of meiosis were revealed. The total number of sperm in the ejaculate in the group with Klinefelter syndrome (0.39± 2.38 (0.00-25.0) million) is significantly lower than in men with dysomy Y (47.15± 77.17 (0.00-265.00) million) and with mosaicism/structural abnormalities Y (8.93 ± 31.72 (0.00-185.00) million). However, it did not significantly differ from patients with 46,XX DSD (0.03 ± 0.08 (0.00-0.375) million). Differences in the frequency of azoospermia were found between groups of patients with Klinefelter syndrome and dysomy Y in karyotype, with Klinefelter syndrome and mosaicism/structural abnormalities of Y, with dysomy Y and with 46,XX DSD. Ejaculate volume parameters significantly differed between patients with mosaics/structural abnormalities (3.6 ± 1.6 (0.2-8.2) ml) and those with 46,XX DSD (2.3 ± 1.4 (0.1-5.1) ml). Conclusion. 90% of patients with sex chromosome DSD and/or unbalanced sex chromosome abnormalities are characterized by primary male infertility caused by severe defects of spermatogenesis, leading to severe nonobstructive azoospermia and oligozoospermia. The most severe spermatogenesis disorders were noted in patients with Klinefelter syndrome, 46,XX testicular DSD and infertile men with unbalanced structural abnormalities of the Y chromosome with extended Y chromosome microdeletions (AZFb+c, AZFb), as well as in patients with structural abnormalities that disrupt the meiotic recombination of sex chromosomes (ring and dicentric Y chromosomes). Less manifested spermatological disorders were noted in the group of patients with Y dysomy, as well as Y-chromosome mosaics and carriers of Y structural abnormalities without deletions at the AZF locus.
2026-02-03 | Multiparametric descriptive and comparative analyses between fertile versus infertile men with severe oligozoospermia and azoospermia
Male infertility represents a major global health concern, often associated with conditions such as severe oligoasthenoteratozoospermia and azoospermia. The aim of the study was to compare clinical, biochemical, and genetic characteristics between infertile men and fertile controls. A prospective case-control study was conducted involving 180 participants, including 90 infertile men (45 with severe oligoasthenoteratozoospermia and 45 with azoospermia) and 90 fertile controls. Semen analysis, testicular ultrasound, vitamin D levels, and genetic testing.were performed. In men with severe oligoasthenoteratozoospermia, significantly reduced mean values were observed for sperm concentration (1.77±2 million/mL), total sperm count (5.59±8 million), total motility (12.64±16%), progressive motility (7.93±12%), vitality (13.64±18%), and normal morphology (1.02±2%) compared to controls. Vitamin D levels were slightly higher in the study group (29.37±9.3 ng/mL) than in controls (25.38±10.2 ng/mL). Average testicular volumes were 12.50±5.47 mL (right) and 12.30±5.09 mL (left). Abnormal echotexture and echogenicity were noted in 24.6% and 31.5% of right testes and 15.6% and 25.5% of left testes, respectively. Y chromosome microdeletions (sY242, sY1291, sY255, sY254) were identified in 4.4% of cases. An abnormal karyotype was found in 7.8% of infertile participants, while 92.2% had a normal karyotype. Compared with fertile men, severe oligoasthenozoospermia and azoospermia show marked alterations in semen, testicular, genetic, and endocrine parameters.
2025-12-17 | Unraveling the human Y chromosome in male health: structural abnormalities and microdeletions with emerging clinical implications
Abstract The human Y chromosome has traditionally been viewed as a gene-poor chromosome, primarily relevant to male reproductive health. However, recent evidence challenges this narrow perspective. This narrative review explores the Y chromosome’s unique structure, evolution, and functional relevance, with a particular focus on the azoospermia factor (AZF) regions and their associated genes. We examine how microdeletions in these regions, along with Y chromosome abnormalities, contribute to male infertility and discuss the underlying genetic mechanisms. Beyond reproduction, emerging evidence connects Y-linked variation and loss of Y (LOY) to cardiometabolic disorders and cancer. In addition, we highlight the importance of current diagnostic techniques used to detect Y chromosome abnormalities, including molecular and cytogenetic methods for infertility diagnosis. Understanding the Y chromosome’s genetic landscape is essential not only for accurate diagnosis but also for advancing precision medicine, forensic genetics, and potential gene-based interventions.
2025-11-30 | The Genetic Landscape of Human Infertility: A Comprehensive Review
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.
small molecules
2026-09-23 | DDX3Y Loss-of-Function Variant in AZFa-Like Non-Obstructive Azoospermia Highlights Gaps in Current Y-Chromosome Microdeletion Testing.
Some men have no sperm in the semen because sperm production in the testis has failed. In selected patients, surgical sperm retrieval may be performed, in which small pieces of testicular tissue are examined to look for rare sperm that could be used for intracytoplasmic sperm injection, a form of IVF in which a single sperm is injected into an egg. Before surgery, men are usually tested for large missing regions on the Y chromosome, including the AZFa region. Complete AZFa deletions are associated with a very poor chance of finding sperm. In this case report, we describe a man with no sperm in the semen, negative standard AZF deletion testing, and no sperm found during microdissection testicular sperm extraction. Later exome sequencing identified a previously unreported stop-gain variant in DDX3Y, a gene located within AZFa and now considered to have moderate evidence for involvement in severe sperm-production failure. Together with previously published cases, this finding illustrates a limitation of standard deletion testing: it cannot detect small gene-level variants. In carefully selected men with an AZFa-like clinical picture, DDX3Y sequence analysis may improve counseling and may help avoid low-yield surgery, but larger studies and economic evaluation are needed.
2026-03-19 | Idiopathic male infertility revisited: can redox endophenotypes reframe the 'idiopathic' label?
Male infertility accounts for nearly half of all infertility cases worldwide, yet up to 30-40% of affected men remain categorized as 'idiopathic', reflecting limitations of conventional diagnostics such as semen analysis, hormonal profiling, karyotyping, and Y-chromosome microdeletion testing. These methods describe sperm quantity and morphology but fail to uncover underlying molecular dysfunctions. Increasing evidence suggests that oxidative stress plays a central role in driving sperm damage, encompassing lipid peroxidation, protein oxidation, mitochondrial dysfunction, DNA fragmentation, and epigenetic instability. Such diverse pathways highlight the inadequacy of a single idiopathic category and necessitate mechanistic stratification. This evidence-based study proposes redox endophenotypes, including hyper- and hypo-oxidative, DNA damage-dominant, mitochondrial dysfunction, epigenetic-redox, and inflammatory-redox phenotypes, as a framework for reclassifying idiopathic male infertility. Each phenotype integrates specific biomarkers, such as oxidation-reduction potential (ORP), isoprostanes, 8-hydroxy-2'-deoxyguanosine, or advanced oxidation protein products, with distinct functional impairments and clinical outcomes. Redox endophenotyping offers diagnostic refinement, guides personalized antioxidant or adjunctive therapy, and informs clinicians and embryologists for appropriate assisted reproductive technology (ART) protocols by counselling and treating the patient, and tailoring sperm selection and preparation strategies. Future directions include multi-center validation of redox assays, integration with omics and exposome data, and application of artificial intelligence for biomarker-driven algorithms. Recognizing redox endophenotypes not only reduces the reliance on exclusionary 'idiopathic' diagnoses but also advances precision andrology, improving patient diagnostics and care, reproductive outcomes and mitigating intergenerational health risks.
2025-11-01 | (143) Bridging Genetics and Management: Hormonal Insights From Men With Azoospermic Factor(AZF) Microdeletions
Abstract Introduction Male-factor infertility contributes to a substantial portion of infertility cases. Genetic factors are believed to play an important role, with Y chromosome microdeletions commonly identified among men with azoospermia. Due to the relatively high prevalence of these deletions, genetic testing for Y chromosome microdeletions has become a routine component of the diagnostic workup for infertile men. While deletions in the AZF (Azoospermia Factor) region are known to impair spermatogenesis, the hormonal profile in this population remains poorly characterized. Hormonal evaluation plays a key role in guiding treatment decisions, including the use of empirical medical therapy (EMT). However, there is limited data on hormonal profiles and EMT usage in men with AZF deletions. Objective We aimed to characterize preoperative hormonal profiles and evaluate the use and outcomes of EMT in men with AZF microdeletions undergoing surgical sperm retrieval. Methods We conducted a multi-institutional retrospective cohort study of men with genetically confirmed AZF micro-deletions, including AZFa, AZFb, AZFc, and combined deletions. Data were collected on preoperative serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), total testosterone (TT), and semen analysis parameters. Additionally, we evaluated patterns of empirical medical therapy (EMT) prescriptions and outcomes of surgical sperm retrieval. Results 40 men with confirmed Y-chromosomal micro-deletions across three academic centers was identified. Patients with SRY translocations (n=4) were excluded from the study. The final cohort included 27 patients with AZFc deletions (75%), 2 with AZFa (6%), 1 with AZFb (3%), and 6 with multilocus deletions (17%). FSH (reference: >7.6 mIU/mL) was elevated in 23 patients (64%), with a median of 19.6 IU/L (IQR: 14.4–25.8). LH (reference: >9 mIU/mL) was elevated in 8 patients (22%), with a median of 14.9 IU/L (IQR: 13.7–20.1). Overall median TT was 243.5 (7.7-379.7). TT was below the lower limit of normal (<300 ng/dL) in 13 patients (36%), with a median of 184 ng/dL (IQR: 133–233). Most patients were azoospermic on semen analysis (86%, n=31/36). Of the seven men treated with EMT, the majority (6/7, 86%) received clomiphene citrate. While there were differences in initial levels of TT, FSH, and LH for those treated with EMT compared to those without EMT, these were not statistically significant (Table 1). Among the 13 patients who underwent surgical sperm retrieval, 6 (46%) had successful outcomes; however, only one had received EMT. Conclusions Men with AZF deletions exhibit varying degrees of hormonal imbalance and rates of empirical medical therapy (EMT) use. Despite EMT, sperm retrieval outcomes were poor, with only 1 out of 7 EMT-treated patients achieving successful sperm retrieval. While hormonal differences were observed between those who received EMT and those who did not, these differences did not reach statistical significance. This is likely due to the limited sample size inherent to this rare patient population. Our findings underscore the variability in hormonal profiles and the unclear efficacy of EMT in promoting spermatogenesis in men with AZF deletions, highlighting the need for further research to inform standardized management strategies. Disclosure No
2024-04-09 | An update on non-obstructive azoospermia; a narrative review
Azoospermia could be either non-obstructive azoospermia (NOA) or obstructive azoospermia (OA). Clinical assessment (testis consistency & volume), laboratory testing (FSH), and genetic testing (karyotype, Y chromosome microdeletion, or specific genetic testing for hypogonadotropic hypogonadism) are used to distinguish NOA (which includes primary and secondary testicular failure) from OA. The treatment of NOA is still empirical. For hypogonadotropic hypogonadism, gonadotropin therapy is the only particular indication that consistently improves semen analysis and rates of conception. The typical treatment consists of gonadotropins (hCG and rFSH) combined, with GnRH therapy maintained for non-responders. Although there is a paucity of level I clinical data, drug therapy combining aromatase inhibitors and gonadotropins may be able to improve outcomes for men who need surgical sperm retrieval. Many trials have been tried for treating NOA, although none of these trials has consistently shown efficacy. This review offers a current overview of the causes, treatments, and management of non-obstructive azoospermia.
2020-11-25 | Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells.
Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA pathogenesis and normal spermatogenic microenvironment. Here, we profile >80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. We show that Sertoli cells, which form the scaffold in the testicular microenvironment, are severely damaged in NOA patients and identify the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature, but exhibit abnormal immune responses, while the cells in idiopathic NOA (iNOA) are physiologically immature. Furthermore, we find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.
proteins
2024-03-04 | A cryptozoospermic infertile male with Y chromosome AZFc microdeletion and low FSH levels due to a simultaneous polymorphism in the FSHB gene: a case report.
Genetic causes account for 10-15% of male factor infertility, making the genetic investigation an essential and useful tool, mainly in azoospermic and severely oligozoospermic men. In these patients, the most frequent findings are chromosomal abnormalities and Y chromosome long arm microdeletions, which cause a primary severe spermatogenic impairment with classically increased levels of FSH. On the other hand, polymorphisms in the FSH receptor (FSHR) and FSH beta chain (FSHB) genes have been associated with different FSH plasma levels, due to variations in the receptor sensitivity (FSHR) or in the production of FSH from the pituitary gland (FSHB). Here, we describe an unusual patient with a combined genetic alteration (classic AZFc deletion of the Y chromosome and TT homozygosity for the -211G>T polymorphism in the FSHB gene (rs10835638)), presenting with cryptozoospermia, severe hypospermatogenesis, and normal LH and testosterone plasma concentrations, but low FSH levels. The patient partially benefitted from treatment with FSH (150 IU three times/week for 6 months) which allowed him to cryopreserve enough motile spermatozoa to be used for intracytoplasmic sperm injection. According to our knowledge, this is the first report of an infertile man with AZFc microdeletion with low FSH plasma concentrations related to homozygosity for the -211G>T polymorphism in the FSHB gene.
2004-08-17 | Gonadotropin treatment of an azoospermic patient with a Y-chromosome microdeletion.
To report on the treatment with recombinant FSH of an azoospermic normogonadotropic patient with a Y-chromosome microdeletion. Case report. An assisted reproduction center. A 32-year-old patient with azoospermia. Histological testicular biopsy, Y-chromosome screening, FSH treatment, and intracytoplasmic sperm injection. Fertilization, embryo development, pregnancy, and delivery. After 6 months of treatment with gonadotropins, a small number of spermatozoa were found in the patient's ejaculate and used for IVF, resulting in a successful twin pregnancy and the delivery of two healthy girls. In this study, treatment with gonadotropins promoted the spermatogenesis process and led to the production of spermatozoa in a normogonadotropic azoospermic patient.
cell therapies
2026-07-29 | Live Birth Following Microdissection Testicular Sperm Extraction and Intracytoplasmic Sperm Injection: A Case Study of a Patient with Non-Obstructive Azoospermia and a Y-chromosome Microdeletion (Ym9; P3, Including AZFb, c Region).
The azoospermia factor (AZF) region on the long arm of the Y chromosome is instrumental in spermatogenesis. In particular, complete deletion of the AZFa, AZFb, and AZFb + c regions is not an indication for microdissection testicular sperm extraction (MD-TESE) as there is no chance of sperm retrieval. This report presents a rare case of a successful live birth, following intracytoplasmic sperm injection (ICSI) using sperm from a patient with a microdeletion of the Y chromosome, including part of the AZFb, c region, who underwent MD-TESE. A 3X-year-old Japanese man with azoospermia was admitted to our hospital in October X. Scrotal ultrasonography, physical examination, and genetic examination resulted in a diagnosis of non-obstructive azoospermia with Y chromosomal microdeletion of Ym-9 P3 (deletion of sequence-tagged site markers [sY2990][sY1197][sy1191], including part of the AZFb region). Thus, ICSI resulted in a successful fertilization and the subsequent birth of a child, suggesting its potential application in the field of in vitro fertilization.
2025-05-28 | Ethnic Differences in Genetic and Epigenetic Factors Related to Male Infertility: A Narrative Review
Male infertility causes problems in 7% of worldwide men which creates major difficulties for reproductive health and family planning. A combination of genetic factors and epigenetic factors with environmental elements and lifestyle choices creates causes of this condition. The treatment options available through assisted reproductive technologies (ART) give hope to couples yet we still know only a few aspects of genetic and epigenetic influences related to male infertility. Studies regarding ethnic differences have demonstrated that infertility incidence rates together with biological causes show substantial variation between different cultural groups. The differences become visible through both genetic mutation frequencies along with alterations in epigenetic controls of reproductive functions. Male infertility suffers from genetic elements that comprise Y-chromosome microdeletions and gene mutations in addition to single nucleotide polymorphisms (SNPs). Fewer studies have been conducted on different ethnic groups because their occurrence rates between populations show significant differences. The development of sperm cells depends critically on epigenetic processes which include DNA methylation and histone modification mechanisms. The modifications affect spermatogenesis and result from genetic factors along with environmental conditions that include diet and lifestyle habits and toxic exposures where these variances differ among ethnic groups. The understanding of genetic and epigenetic variations across ethnic populations creates essential effects on diagnosing and treating male infertility. The use of ethnic-specific profiles for diagnostic and treatment selection enhances both accuracy rates and treatment success outcomes. The analysis of ethnic differences makes the possibility of developing targeted reproductive healthcare initiatives along with methods to decrease reproductive health inequality. The article investigates the ways that genetic along epigenetic variations between ethnic populations affect male infertility rates. This review brings together existing knowledge while demonstrating unmet needs to underline the need for ethnic perspectives in studies involving infertility. The research advances methods for developing better specific diagnoses and treatment options for male infertility worldwide.
2024-09-11 | Familial DMRT1-related non-obstructive azoospermia: a case report.
To report an exceptional case of male-to-male transmission of genetically based non-obstructive azoospermia (NOA) and varicocele through a naturally obtained pregnancy. A father and his son were both diagnosed with NOA after centrifugation and varicocele. The father has no other clinical concerns apart from infertility, detected after many attempts of having another child, but given his urological situation (bilateral varicocele and NOA) assisted reproductive techniques were discouraged. After genetic counseling, several genetic-chromosomal analyses were carried out in the son (karyotype, chromosome Y microdeletions, CFTR screening, NGS infertility panels, and finally array-CGH). After a series of inconclusive tests, array-CGH detected a deletion of 224-283 kb (del9p24.3) involving part of the KANK1 and DMRT1 genes, inherited from the father. Haploinsufficiency of DMRT1 was therefore considered the determining factor in the development of azoospermia in the family by a loss of function mechanism. The confirmation of father-to-son transmission of a deletion including DMRT1 represents an important point for clinicians dealing with male infertility, even when complete azoospermia is repetitively detected, and must be of hope for a relevant portion of men. Inclusion criteria for the access to assisted reproductive techniques may also be reconsidered and worthy of a greater number of clinical insights. Finally, since DMRT1 alterations have been associated with NOA and abnormal testicular development, but not specifically with varicocele, further studies are required to validate this issue, as varicocele may have played a crucial role in this case.
2021-12-03 | Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis.
Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.
2021-10-12 | Complex Y chromosome anomalies in an infertile male.
Y chromosome anomalies are closely associated with non-obstructive azoospermia (NOA), a major etiology in male infertility. Klinefelter syndrome (KS) and Y chromosome microdeletions are some of the well-identified genetic defects in this regard, while Y chromosome aneuploidies have been reported to be susceptive. We report the rare case of a patient presenting with three complex genetic defects: mosaic Y chromosome aneuploidy; loss of the heterochromatin region in the q arm of the Y chromosome (Yqh-); and azoospermia factor C subregion (AZFc) microdeletion. The patient reported he had been subfertile for five years. Semen analysis confirmed total azoospermia along with an unaffected hormonal profile for serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels. Since the microdeletion analysis of azoospermia factor (AZF) region revealed the presence of three microdeletions in the AZFc region, the patient was offered intracytoplasmic sperm injection (ICSI) upon the retrieval of sperm by testicular sperm extraction (TESE) as the best possible assisted reproductive treatment (ART) option. It was further suggested to carry out pre-implantation genetic screening (PGS) in order to facilitate the transfer of only female embryos, thus preventing the dissemination of Y chromosomal anomalies.
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