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Query: UMLS:C0021359 (infertility)
 26,075 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An overview is given about the current knowledge and research activities on the molecular analysis of interstitial deletions in the euchromatic part of the long arm of the human Y chromosome (Yq11). These mutations are associated with the male specific phenotype of azoospermia and severe oligozoospermia. The fact is stressed that only "de novo" microdeletions in Yq11 are of any diagnostic value in the infertility clinic because numerous polymorphic deletion events in Yq11 have also been reported. Three different "de novo" Yq11 microdeletions associated with male infertility are now found repeatedly (31 cases) in more than 700 patients. They strongly support the presence of at least three spermatogenesis loci in Yq11. They have been designated as AZFa, AZFb, and AZFc. Each of them should contain at least one Y gene functional in spermatogenesis and, if mutated, it should induce the same sterile phenotype as the corresponding AZF locus. These genes have not yet been found. However, some candidate genes exist: RBM for AZFb. DAZ and SPGY for AZFc. It is remarkable that all three encode testis specific RNA binding proteins with a similar sequence structure. Their structure and potential relationship is disussed.
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PMID:Human Y chromosome deletions in Yq11 and male fertility. 936 58

Y chromosomal spermatogenesis loci in Yq11 are disrupted with a frequency of 5-20% in men suffering from idiopathic infertility (azoospermia or severe oligozoospermia). They were designated azoospermia factors (AZFa, AZFb, AZFc). An efficient schedule for their molecular diagnosis in each infertility clinic is presented. In addition, I will include our current knowledge about their biological function during human germ cell development and a description of their pathology in men suffering from deletion of one or more AZF loci. Each Y gene expressed in testis tissue and located in Yq11, in a position overlapping one of the AZF loci, is an AZF candidate gene. Their diagnostic analysis will be described in a separate section. The clinical diagnosis of AZF candidate genes cannot substitute for diagnosis of the genetically defined AZF loci. Therefore, analysis of candidate genes is aimed at answering the question of whether mutations in their exon structures are able to induce the same pathological phenotypes as deletion of the corresponding AZF locus. Only after these gene mutations have been analysed can the AZF candidate gene be designated as a real AZF gene. Therefore, the basic aim of our current research is isolation and identification of all AZF genes.
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PMID:Genetics of idiopathic male infertility: Y chromosomal azoospermia factors (AZFa, AZFb, AZFc). 969 17

Human chromosome deletions in Yq11 seem to occur frequently as de novo mutation events in men with idiopathic azoospermia or severe oligozoospermia. However, the molecular extensions of these deletions are variable. They can be large and therefore visible under the microscope or small, not visible under the microscope, and containing the deletion of one or more DNA loci recently mapped in an apparently consecutive order along the Yq11 chromosome region. The results of 20 extensive microdeletion screening programmes have now corroborated the prevalence of the deletion of three non-overlapping DNA regions in proximal, middle and distal Yq11, which were designated earlier as AZFa, AZFb and AZFc. Deletions of single DNA loci were also reported, but as de novo and as polymorphic mutation events. Their clinical significance with regard to the men's infertility should therefore initially be handled with caution. Multiple Y genes expressed in human testis have now been mapped to each AZF region. At least one of them should be functional in human spermatogenesis and, if mutated, cause azoospermia. However, gene-specific mutations leading to the azoospermia phenotype have not yet been found for any of these AZF candidate genes. This might raise the question as to whether an AZF gene really exists in Yq11 or if the azoospermia phenotypes are only observed after deletion of a complete AZF region, after deletion of its complete gene content.
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PMID:Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. 973 30

Cytogenetic and molecular deletion analyses of azoospermic and oligozoospermic males have suggested the existence of AZoospermia Factor(s) (AZF) residing in deletion intervals 5 and 6 of the human Y-chromosome and coinciding with three functional regions associated with spermatogenic failure. Nonpolymorphic microdeletions in AZF are associated with a broad spectrum of testicular phenotypes. Unfortunately, Sequence Tagged Sites (STSs) employed in screening protocols range broadly in number and mapsite and may be polymorphic. To thoroughly analyze the AZF region(s) and any correlations that may be drawn between genotype and phenotype, we describe the design of nine multiplex PCR reactions derived from analysis of 136 loci. Each multiplex contains 4-8 STS primer pairs, amplifying a total of 48 Y-linked STSs. Each multiplex consists of one positive control: either SMCX or MIC2. We screened four populations of males with these STSs. Population I consisted of 278 patients diagnosed as having significant male factor infertility: either azoospermia, severe oligozoospermia associated with hypogonadism and spermatogenic arrest or normal sperm counts associated with abnormal sperm morphology. Population II consisted of 200 unselected infertile patients. Population III consisted of 36 patients who had previously been shown to have aneuploidy, cytological deletions or translocations involving the Y-chromosome or normal karyotypes associated with severe phenotype abnormalities. Population IV consisted of 920 fertile (control) males. The deletion rates in populations I, II and III were 20.5%, 7% and 58.3%, respectively. A total of 92 patients with deletions were detected. The deletion rate in population IV was 0.87% involving 8 fertile individuals and 4 STSs which were avoided in multiplex panel construction. The ability of the nine multiplexes to detect pathology associated microdeletions is equal to or greater than screening protocols used in other studies. Furthermore, the data suggest a fourth AZF region between AZFb and AZFc, which we have termed AZFd. Patients with microdeletions restricted to AZFd may present with mild oligozoospermia or even normal sperm counts associated with abnormal sperm morphology. Though a definitive genotype/phenotype correlation does not exist, large deletions spanning multiple AZF regions or microdeletions restricted to AZFa usually result in patients with Sertoli Cell Only (SCO) or severe oligozoospermia, whereas microdeletions restricted to AZFb or AZFc can result in patients with phenotypes which range from SCO to moderate oligozoospermia. The panel of nine multiplexed reactions, the Y-deletion Detection System (YDDS), provides a fast, efficient and accurate method of assessing the integrity of the Y-chromosome. To date, this study provides the most extensive screening of a proven fertile male population in tandem with 514 infertile males, derived from three different patient selection protocols.
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PMID:Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. 1023 Aug 14

Sperm cells can be retrieved directly from the testis (testicular sperm extraction [TESE] procedure) and used for intracytoplasmic sperm injection (ICSI), circumventing underlying spermatogenetic defects. Thus, it is important that added information be available on the genetic defects in men undergoing TESE for the ICSI procedure and on the transmission of genetic factors associated with infertility to the offspring. We report a three-generation genetic analysis of a family with a case of male factor infertility. The proband, previously diagnosed as infertile, was physically examined and laboratory tested for gonadotrophic hormones, semen analysis, karyotype and Y-chromosome microdeletion screening in the blood and testis. The Y-chromosome microdeletion screening was performed by multiplex polymerase chain reaction with 20 Y-chromosome sequenced, tagged sites located at the Y chromosome. A microdeletion including the AZF-c region was detected in the azoospermic patient. His father, four brothers, and three offspring born after ICSI also underwent Y-chromosome microdeletion screening. The genetic analysis of the male members of the patient's family did not reveal similar microdeletions. The newborn male was found to bear a Y-chromosome microdeletion similar to that of his father. The fertilization capacity of the proband testicular microdeleted spermatozoa by the ICSI procedure is described. The transfer of the genetic defect raises the possibility that the son will have the same fertility problem as his father.
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PMID:Three-generation evaluation of Y-chromosome microdeletion. 1038 19

Genetic causes of infertility are probably not rare. Today only a fraction of genes directly or indirectly involved in reproduction including sex determination and differentiation are known. Nevertheless, the list of well-defined genetic disorders impairing fertility is impressing already today and growing rapidly. Gonosomal aneuploidy and structural rearrangements represent a significant portion of the genetic causes of infertility in both sexes. Other chromosomal conditions include autosomal balanced structural changes (e.g. translocations), probably due to pairing disturbances of the affected chromosomes during meiosis. Some fundamental mechanisms in sex determination and differentiation have been characterized in recent years. Mutations in some of the genes involved in this process may lead to familial infertility. Genetic defects in gametogenesis of both sexes are currently being investigated using mouse models. Male specific causes of infertility include microdeletion within the AZF region of the euchromatic part of the long arm of the Y chromosome and obstructive azoospermia due congenital aplasia of the vas deferens in the presence of mutations in the CFTR gene.
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PMID:[Is sterility a genetic burden?]. 1040 1

This study reports on the validation of a diagnostic screening programme for Yq deletions in a population of infertile men. First, an unselected group of 402 intracytoplasmic sperm injection (ICSI) candidate patients was screened prospectively by means of three polymerase chain reactions (PCR) each with one marker in the region AZFa, AZFb or AZFc. With this screening strategy, eight males (2.2%) were found to carry a deletion in Yq11. Secondly, a subgroup of males were further analysed by multiplex PCR with 27 sequence-tagged sites. In this group of 229 cytogenetically normal males with azoospermia, cryptozoospermia or extreme oligozoospermia, including some patients with varicocele or a history of cryptorchidism, only one additional microdeleted patient was found with the multiplex PCR. Hence we obtained a frequency of 2.2% (9/402) or 4% (9/229) in the unselected and selected patient groups respectively. We conclude that in a diagnostic programme for Yq deletions in ICSI candidates it might be sufficient to use only four markers representing the three AZF regions and a more distal region in AZFc. In this way, it is possible to detect most, if not all, Yq deletions which might be the causal factor in the patient's infertility.
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PMID:Validation of a simple Yq deletion screening programme in an ICSI candidate population. 1142 Mar 93

Deletions of the AZFc interval of the human Y chromosome are found in >5% of male patients with idiopathic infertility and are associated with a severely reduced sperm count. The most common deletion type is large (>1 Mb) and removes members of the Y-borne testis-specific gene families of BPY2, CDY1, DAZ, PRY, RBMY2 and TTY2, which are candidate AZF genes. Four exceptional individuals who have transmitted a large AZFc deletion naturally to their infertile sons have, however, been described. In three cases, transmission was to an only son, but in the fourth case a Y chromosome, shown to be deleted for all copies of DAZ, was transmitted from a father to his four infertile sons. Here we present a second family of this latter type and demonstrate that an AZFc-deleted Y chromosome lacking not only DAZ, but also BPY2 and CDY1, has been transmitted from a father to his three infertile sons. Polymerase chain reaction (PCR) and Southern blot analyses revealed no difference in the size of the AZFc deletion in the father and his sons. We propose that the father carries rare alleles of autosomal or X-linked loci which suppress the infertility that is frequently associated with the absence of AZFc.
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PMID:The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. 1095 50

Substantial involvement of the Y chromosome in sexual development and spermatogenesis has been demonstrated. Over the last decade, varying extent of Y chromosome microdeletions have been identified among infertile patients with azoospermia or oligozoospermia. These microdeletions were clustered in three main regions named AZFa, AZFb, and AZFc. Analysis of the Y chromosome microdeletion was found to be of prognostic value in cases of infertility, both in terms of clinical management as well as for understanding the aetiology of the spermatogenesis impairment. However, the accumulated data are difficult to analyse, due to the variable extent of these deletions, the different sequence-tagged sites (STS) used to detect the microdeletions, and the non-uniformity of the histological terminology used by different investigators. This debate discusses the chances of finding testicular spermatozoa in men with a varying extent of Y chromosome microdeletions. The genotype and germ cell findings in men with AZFa microdeletions as well as those that include more than a single AZF region are reviewed, as is the effect of Y chromosome AZF microdeletions on the maturity of the Sertoli cells.
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PMID:The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. 1122 2

Varicocele is the most common clinical finding in infertile men but controversy continues to surround the utility of its treatment. An increased response of FSH to gonadotrophin-releasing hormone testing has been described in patients with varicocele, while the co-influence of Yq chromosome microdeletions in the infertility associated to this pathology is still under investigation. We studied 30 patients with first- and second-grade varicocele, 15 idiopathic oligozoospermic men and 21 age-matched healthy controls. All subjects underwent testicular Doppler ultrasonography, semen analysis, gonadotrophin-releasing hormone testing and baseline blood sampling for total and free testosterone, PRL, 17beta-estradiol, SHBG evaluation and Yq chromosome analysis. Apart from FSH, no difference in baseline hormonal levels was found between the groups. The patients with varicocele showed both an increased basal (p=0.007) and GnRH-induced FSH response (peak and AUC) (p=0.004) in comparison with the controls, while the idiopathic oligozoospermic men had only higher GnRH-induced FSH AUC (p=0.04). In the varicocele group, FSH peaks after GnRH testing correlated positively with the grade of disease (r=0.42, p=0.02) and negatively with sperm count (r=-0.50, p=0.005) and bilateral testis volume (r=-0.52, p=0.005). Sperm count and sperm motility were similarly significantly reduced both in patients with varicocele and in patients with idiopathic oligozoospermia in comparison with healthy controls. Yq chromosome analysis by sequence-tagged site PCR revealed no microdeletion in the AZF regions in any subject studied. Given the quite small number of subjects studied, our overall findings can only prompt us to suggest a possible causal role of varicocele in the impairment of spermatogenesis in our patients. Furthermore, although a genetic co-influence (i.e. Yq microdeletions) does not seem to be involved in the pathogenesis of infertility in men with varicocele and mild to moderate oligozoospermia, genetic screening seems to be advisable, especially in those patients who present a severe impairment of sperm count, as has been suggested by recent literature data.
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PMID:Lack of evidence of a genetic origin in the impaired spermatogenesis of a patient cohort with low-grade varicocele. 1138 7


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