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Clinics (Sao Paulo, Brazil) 2013The misconception that infertility is typically associated with the female is commonly faced in the management of infertile men. It is uncommon for a patient to present... (Review)
Review
The misconception that infertility is typically associated with the female is commonly faced in the management of infertile men. It is uncommon for a patient to present for an infertility evaluation with an abnormal semen analysis report before an extensive female partner workup has been performed. Additionally, a man is usually considered fertile based only on seminal parameters without a physical exam. This behavior may lead to a delay in both the exact diagnosis and in possible specific infertility treatment. Moreover, male factor infertility can result from an underlying medical condition that is often treatable but could possibly be life-threatening. The responsibility of male factor in couple's infertility has been exponentially rising in recent years due to a comprehensive evaluation of reproductive male function and improved diagnostic tools. Despite this improvement in diagnosis, azoospermia is always the most challenging topic associated with infertility treatment. Several conditions that interfere with spermatogenesis and reduce sperm production and quality can lead to azoospermia. Azoospermia may also occur because of a reproductive tract obstruction. Optimal management of patients with azoospermia requires a full understanding of the disease etiology. This review will discuss in detail the epidemiology and etiology of azoospermia. A thorough literature survey was performed using the Medline, EMBASE, BIOSIS, and Cochrane databases. We restricted the survey to clinical publications that were relevant to male infertility and azoospermia. Many of the recommendations included are not based on controlled studies.
Topics: Azoospermia; Humans; Infertility, Male; Male; Semen Analysis
PubMed: 23503951
DOI: 10.6061/clinics/2013(sup01)03 -
International Journal of Molecular... Mar 2021Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct... (Review)
Review
Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.
Topics: Alleles; Animals; Azoospermia; Biomarkers; Chromosome Deletion; Chromosomes, Human, Y; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Phenotype; Spermatogenesis; Exome Sequencing
PubMed: 33806855
DOI: 10.3390/ijms22063264 -
Ugeskrift For Laeger Nov 2021Impaired male fertility contributes to at least 50% of cases of couple infertility. Azoospermia is found in 1-2% of the male population. In the diagnostic workup,... (Review)
Review
Impaired male fertility contributes to at least 50% of cases of couple infertility. Azoospermia is found in 1-2% of the male population. In the diagnostic workup, genetic and endocrine as well as lifestyle factors may be considered. Spermatozoa can be retrieved surgically in many cases of azoospermia, aspermia and difficult cases of retrograde ejaculation. Such spermatozoa can be used for injection into the oocytes of the female partners by intracytoplasmic sperm injection. Treatment with follicle stimulating hormone is only indicated in hypogonadotrophic hypogonadism. This review is a summarisation of the current male infertility treatment modalities.
Topics: Azoospermia; Female; Humans; Hypogonadism; Infertility, Male; Male; Sperm Injections, Intracytoplasmic; Spermatozoa; Testis
PubMed: 34852902
DOI: No ID Found -
Nature Communications Nov 2020Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA...
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.
Topics: Adult; Azoospermia; Gene Expression Profiling; Humans; Male; Sertoli Cells; Single-Cell Analysis; Spermatogenesis; Spermatozoa; Testis
PubMed: 33173058
DOI: 10.1038/s41467-020-19414-4 -
Nature Communications Dec 2022Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the...
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.
Topics: Humans; Male; Animals; Mice; Azoospermia; Testis; Infertility, Male; Spermatogenesis
PubMed: 36572685
DOI: 10.1038/s41467-022-35661-z -
Andrology Jan 2014The molecular diagnosis of Y-chromosomal microdeletions is a common routine genetic test which is part of the diagnostic workup of azoospermic and severe oligozoospermic... (Review)
Review
The molecular diagnosis of Y-chromosomal microdeletions is a common routine genetic test which is part of the diagnostic workup of azoospermic and severe oligozoospermic men. Since 1999, the European Academy of Andrology (EAA) and the European Molecular Genetics Quality Network (EMQN) have been actively involved in supporting the improvement of the quality of the diagnostic assays by publication of the laboratory guidelines for molecular diagnosis of Y-chromosomal microdeletions and by offering external quality assessment trials. The present revision of the 2004 laboratory guidelines summarizes all the clinical novelties related to the Y chromosome (classic, partial and gene-specific deletions, genotype-phenotype correlations, methodological issues) and provides an update on the results of the quality control programme. These aspects also reflect the consensus of a large group of specialists present at a round table session during the recent Florence-Utah-Symposium on 'Genetics of male infertility' (Florence, 19-21 September, 2013). During the last 10 years the gr/gr deletion has been demonstrated as a significant risk factor for impaired sperm production. However, the screening for this deletion type in the routine diagnostic setting is still a debated issue among experts. The original basic protocol based on two multiplex polymerase chain reactions remains fully valid and appropriate for accurate diagnosis of complete AZF deletions and it requires only a minor modification in populations with a specific Y chromosome background. However, in light of novel data on genotype-phenotype correlations, the extension analysis for the AZFa and AZFb deletions is now routinely recommended. Novel methods and kits with excessively high number of markers do not improve the sensitivity of the test, may even complicate the interpretation of the results and are not recommended. Annual participation in an external quality control programme is strongly encouraged. The 12-year experience with the EMQN/EAA scheme has shown a steep decline in diagnostic (genotyping) error rate and a simultaneous improvement on reporting practice.
Topics: Humans; Male; Azoospermia; Chromosome Deletion; Chromosomes, Human, Y; Genetic Counseling; Genetic Testing; Genotype; Genotyping Techniques; Infertility, Male; Molecular Diagnostic Techniques; Oligospermia; Sex Chromosome Aberrations; Sex Chromosome Disorders of Sex Development
PubMed: 24357628
DOI: 10.1111/j.2047-2927.2013.00173.x -
Andrology Nov 2022Genetic causes that lead to spermatogenetic failure in patients with nonobstructive azoospermia (NOA) have not been yet completely established.
BACKGROUND
Genetic causes that lead to spermatogenetic failure in patients with nonobstructive azoospermia (NOA) have not been yet completely established.
OBJECTIVE
To identify low-frequency NOA-associated single nucleotide variants (SNVs) using whole-genome sequencing (WGS).
MATERIALS AND METHODS
Men with various types of NOA (n = 39), including samples that had been previously tested with whole-exome sequencing (WES; n = 6) and did not result in diagnostic conclusions. Variants were annotated using the Ensembl Variant Effect Predictor, utilizing frequencies from GnomAD and other databases to provide clinically relevant information (ClinVar), conservation scores (phyloP), and effect predictions (i.e., MutationTaster). Structural protein modeling was also performed.
RESULTS
Using WGS, we revealed potential NOA-associated SNVs, such as: TKTL1, IGSF1, ZFPM2, VCX3A (novel disease causing variants), ESX1, TEX13A, TEX14, DNAH1, FANCM, QRICH2, FSIP2, USP9Y, PMFBP1, MEI1, PIWIL1, WDR66, ZFX, KCND1, KIAA1210, DHRSX, ZMYM3, FAM47C, FANCB, FAM50B (genes previously known to be associated with infertility) and ALG13, BEND2, BRWD3, DDX53, TAF4, FAM47B, FAM9B, FAM9C, MAGEB6, MAP3K15, RBMXL3, SSX3 and FMR1NB genes, which may be involved in spermatogenesis.
DISCUSSION AND CONCLUSION
In this study, we identified novel potential candidate NOA-associated genes in 29 individuals out of 39 azoospermic males. Note that in 5 out of 6 patients subjected previously to WES analysis, which did not disclose potentially causative variants, the WGS analysis was successful with NOA-associated gene findings.
Topics: Argonaute Proteins; Azoospermia; Calcium-Binding Proteins; DNA Helicases; Humans; Immunoglobulins; Male; Membrane Proteins; Mutation; N-Acetylglucosaminyltransferases; Nuclear Proteins; Nucleotides; Transcription Factors; Transketolase; Exome Sequencing
PubMed: 36017582
DOI: 10.1111/andr.13269 -
American Journal of Human Genetics Mar 2022Non-obstructive azoospermia (NOA) is a severe and frequent cause of male infertility, often treated by testicular sperm extraction followed by intracytoplasmic sperm...
Non-obstructive azoospermia (NOA) is a severe and frequent cause of male infertility, often treated by testicular sperm extraction followed by intracytoplasmic sperm injection. The aim of this study is to improve the genetic diagnosis of NOA, by identifying new genes involved in human NOA and to better assess the chances of successful sperm extraction according to the individual's genotype. Exome sequencing was performed on 96 NOA-affected individuals negative for routine genetic tests. Bioinformatics analysis was limited to a panel of 151 genes selected as known causal or candidate genes for NOA. Only highly deleterious homozygous or hemizygous variants were retained as candidates. A likely causal defect was identified in 16 genes in a total of 22 individuals (23%). Six genes had not been described in man (DDX25, HENMT1, MCMDC2, MSH5, REC8, TDRKH) and 10 were previously reported (C14orf39, DMC1, FANCM, GCNA, HFM1, MCM8, MEIOB, PDHA2, TDRD9, TERB1). Seven individuals had defects in genes from piwi or DNA repair pathways, three in genes involved in post-meiotic maturation, and 12 in meiotic processes. Interestingly, all individuals with defects in meiotic genes had an unsuccessful sperm retrieval, indicating that genetic diagnosis prior to TESE could help identify individuals with low or null chances of successful sperm retrieval and thus avoid unsuccessful surgeries.
Topics: Azoospermia; DNA Helicases; DNA-Binding Proteins; Humans; Male; Sperm Retrieval; Testis; Exome Sequencing
PubMed: 35172124
DOI: 10.1016/j.ajhg.2022.01.011 -
International Journal of Molecular... May 2023Male infertility is a global issue that seriously affects reproductive health. This study aimed to understand the underlying causes of idiopathic non-obstructive...
Male infertility is a global issue that seriously affects reproductive health. This study aimed to understand the underlying causes of idiopathic non-obstructive azoospermia (iNOA), which is a type of male infertility with unknown origins that accounts for 10-15% of cases. By using single-cell analysis techniques, we aimed to uncover the mechanisms of iNOA and gain insight into the cellular and molecular changes in the testicular environment. In this study, we performed bioinformatics analysis using scRNA-seq and microarray data obtained from the GEO database. The analysis included techniques such as pseudotime analysis, cell-cell communication, and hdWGCNA. Our study showed a significant difference between the iNOA and the normal groups, indicating a disorder in the spermatogenic microenvironment in iNOA. We observed a reduction in the proportion of Sertoli cells and blocked germ cell differentiation. Additionally, we found evidence of testicular inflammation related to macrophages and identified and as potential biomarkers for iNOA.
Topics: Humans; Male; Azoospermia; Testis; Spermatogenesis; Infertility, Male; Orchitis; Inflammation; Single-Cell Analysis; Heat-Shock Proteins
PubMed: 37240164
DOI: 10.3390/ijms24108819 -
Fertility and Sterility Nov 2015
Topics: Attitude of Health Personnel; Azoospermia; Communication; Counseling; Female; Grief; Humans; Infertility, Male; Male; Physician-Patient Relations; Pregnancy; Sperm Retrieval; Treatment Failure
PubMed: 26439761
DOI: 10.1016/j.fertnstert.2015.09.028