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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 -
Frontiers in Immunology 2023Up to 50% of infertility is caused by the male side. Varicocele, orchitis, prostatitis, oligospermia, asthenospermia, and azoospermia are common causes of impaired male... (Review)
Review
Up to 50% of infertility is caused by the male side. Varicocele, orchitis, prostatitis, oligospermia, asthenospermia, and azoospermia are common causes of impaired male reproductive function and male infertility. In recent years, more and more studies have shown that microorganisms play an increasingly important role in the occurrence of these diseases. This review will discuss the microbiological changes associated with male infertility from the perspective of etiology, and how microorganisms affect the normal function of the male reproductive system through immune mechanisms. Linking male infertility with microbiome and immunomics can help us recognize the immune response under different disease states, providing more targeted immune target therapy for these diseases, and even the possibility of combined immunotherapy and microbial therapy for male infertility.
Topics: Male; Humans; Infertility, Male; Oligospermia; Azoospermia; Genitalia, Male; Varicocele
PubMed: 36895560
DOI: 10.3389/fimmu.2023.1139450 -
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 -
Human Reproduction (Oxford, England) Jan 2023The amount of single-cell RNA-sequencing (scRNA-seq) data produced in the field of human male reproduction has steadily increased. Transcriptional profiles of thousands... (Review)
Review
The amount of single-cell RNA-sequencing (scRNA-seq) data produced in the field of human male reproduction has steadily increased. Transcriptional profiles of thousands of testicular cells have been generated covering the human neonatal, prepubertal, pubertal and adult period as well as different types of male infertility; the latter include non-obstructive azoospermia, cryptozoospermia, Klinefelter syndrome and azoospermia factor deletions. In this review, we provide an overview of transcriptional changes in different testicular subpopulations during postnatal development and in cases of male infertility. Moreover, we review novel concepts regarding the existence of spermatogonial and somatic cell subtypes as well as their crosstalk and provide corresponding marker genes to facilitate their identification. We discuss the potential clinical implications of scRNA-seq findings, the need for spatial information and the necessity to corroborate findings by exploring other levels of regulation, including at the epigenetic or protein level.
Topics: Adult; Infant, Newborn; Humans; Male; Spermatogenesis; Azoospermia; Testis; Infertility, Male; Fertility; Stem Cells; RNA
PubMed: 36409992
DOI: 10.1093/humrep/deac245 -
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 -
Journal of Endocrinological... Jun 2023Infertility, which is defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourses, affects about 15-20% of couples worldwide... (Review)
Review
BACKGROUND
Infertility, which is defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourses, affects about 15-20% of couples worldwide and a male factor is involved in about half of the cases. The development of assisted reproductive technology (ART) made it possible to conceive also to individuals affected from severe oligospermia or azoospermia. However, the impact of the male factor on embryo development, implantation, prevalence of chromosomal abnormalities, genetic and epigenetic alterations, and clinical and obstetric outcomes is still controversial.
PURPOSE
This narrative review examines the indications, minimum access criteria, and outcomes by individual ART technique in relation to the male factor.
Topics: Pregnancy; Female; Humans; Male; Infertility, Male; Reproductive Techniques, Assisted; Azoospermia; Chromosome Aberrations; Infertility
PubMed: 36633791
DOI: 10.1007/s40618-022-02000-4 -
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 -
The New England Journal of Medicine Aug 2021P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells,...
BACKGROUND
P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility.
METHODS
We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing.
RESULTS
Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in : the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A→T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying mutations.
CONCLUSIONS
Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility. (Funded by Innovation Fund Denmark and others.).
Topics: Adult; Azoospermia; Biopsy; Exoribonucleases; Gene Expression; Humans; Infertility, Male; Male; Meiosis; Mutation; Phenotype; Polymerase Chain Reaction; RNA, Small Interfering; Sequence Analysis, RNA; Testis; Exome Sequencing
PubMed: 34347949
DOI: 10.1056/NEJMoa2028973