Genetic causes of male infertility.
TL;DR: This review will report and discuss the genetic causes of male infertility known up to date and analyse genetic polymorphisms possibly associated with male infertility.
About: This article is published in Reproductive Toxicology.The article was published on 2006-08-01. It has received 255 citations till now. The article focuses on the topics: Infertility & Male infertility.
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TL;DR: This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.
Abstract: Context: An explosive growth in Y chromosome long arm (Yq) microdeletion testing demand for male infertility occurred in the past few years. However, despite the progresses in the biology of this chromosome, a number of molecular and clinical concerns are not supported by definitive data. Objective: The objective was to provide information on the type and prevalence of microdeletions in infertile males, indication for testing, genotype-phenotype correlation, sperm aneuploidies, and genetic counseling. Design and Setting: We performed a prospective study from January 1996 to December 2005 in an academic clinic. Patients: We studied 3073 consecutive infertile men, of which 625 were affected by nonobstructive azoospermia and 1372 were affected by severe oligozoospermia. Ninety-nine patients with microdeletions are described here. Main Outcome Measures: Yq microdeletions, seminal analysis, reproductive hormones, testicular cytology/histology, and sperm sex chromosomes aneuploidies were used as outcome measure...
247 citations
TL;DR: These findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis.
169 citations
TL;DR: A comprehensive interdisciplinary examination of recent developments in genetic, endocrine, and neurocognitive science, including the study of animal models is presented, providing a number of recommendations for improving the effectiveness of research and clinical practice.
Abstract: Although first identified over 70 years ago, Klinefelter syndrome (KS) continues to pose substantial diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as few as 25% of patients with KS are accurately diagnosed and most of these diagnoses are not made until adulthood. Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role. For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype. KS is also associated with more general health markers, including higher morbidity and mortality rates and lower socioeconomic status (which likely affect both morbidity and mortality). In addition, hypogonadism is associated with greater risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors. Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy have not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes. This review presents a comprehensive interdisciplinary examination of recent developments in genetic, endocrine, and neurocognitive science, including the study of animal models. It provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence.
166 citations
TL;DR: While the association of the complete AZFc deletion with spermatogenic failure is well established, the role of partialAZFc deletions on sperMatogenesis and male infertility is still controversial.
Abstract: Infertility is a major health problem today, affecting about 15.0% of couples trying to have a child. Impaired fertility of the male is causative in 20.0% of infertile couples and contributory in up to another 30.0–40.0%. Infertility already affects about 5.0–7.0% of the general male population and may further increase in the future, considering the apparent trend of declining sperm count in industrialized countries. Despite enormous progress in the understanding of human reproductive physiology, the underlying cause of male infertility remains undefined in about 50.0% of cases, which are referred to as idiopathic infertility [1]. Most idiopathic cases are likely to be of genetic origin because the number of genes involved in human spermatogenesis is probably over 1 thousands. At present, only a few of the genes implicated in the processes of testis determination, testis descent and spermatogenesis have routine clinical importance. These include the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whose mutations cause cystic fibrosis and absence of vas deferens and the androgen receptor (AR) gene, whose mutations cause the androgen insensitivity syndrome and spermatogenic damage.
Common Genetic Causes of Male Infertility. Chromosomal anomalies and microdeletions of the azoospermia factor (AZF) regions of the Y chromosome are the only commonly known genetic causes of spermatogenic failure. The frequency of these two genetic anomalies increases with the severity of the spermatogenic defect, reaching up to an overall 30.0% (15.0% karyotype abnormalities and 15.0% of AZF microdeletions) in azoospermic men.
Sex chromosome aneuploidies, such as 47,XXY (Klinefelter’s syndrome), 47,XYY and 46,XX males are the most common chromosome anomalies occurring at birth and in the population of infertile males [2]. Klinefelter’s syndrome is a form of primary testicular failure with a high prevalence in infertile men, up to 5.0% in severe oligozoospermia and 10.0% in azoospermia.
Y chromosome microdeletions represent the etiological factor of 10.0–15.0% of idiopathic azoospermia and severe oligozoospermia [3]. The frequency of AZF deletions in infertile men ranges from 5.0 to 20.0% in worldwide surveys [4]. Y chromosome microdeletions are found almost exclusively in patients with azoospermia or severe oligozoospermia [5]. The prevalence of Y chromosome microdeletions in the infertile males from the Republic of Macedonia is 6.4%, in patients with azoospermia 16.7% and 2.8% in those with severe oligozoospermia [6]. Deletions most frequently involve the AZFc region, less frequently the AZFb region, and only rarely the AZFa region. The most frequent deletions in Macedonian males are AZFc deletions, while AZFa deletions have not been detected [7,8].
Partial deletions within the AZFc region (gr/gr and b2/b3) that remove smaller portions of the AZFc region (1.6 and 1.8 Mb) are much more common and are present at various frequencies in different Y chromosome haplogroups [9]. While the association of the complete AZFc deletion with spermatogenic failure is well established, the role of partial AZFc deletions on spermatogenesis and male infertility is still controversial.
In addition to deletions, different duplications at the AZFc region have been reported. Duplications can occur on a chromosome with a partial AZFc deletion and generate a chromosome with four DAZ genes, but lacking some sequence tagged site (STS) markers [10,11]. Recently, an AZFc partial duplication has been shown to be a risk factor for male infertility in Taiwan [12].
Screening for Common Genetic Causes of Male Infertility by Quantitative Fluorescent-Polymerase Chain Reaction. Screening for chromosomal abnormalities is usually done by cytogenetic analysis and for AZF deletions by polymerase chain reaction (PCR) analysis of several STSs in the three AZF regions. Recently, we described a multiplex quantitative fluorescent (QF)-PCR method that allows simultaneous detection of the most common genetic causes of male infertility, i.e., sex chromosomal aneuploidies and AZFc and AZFb deletions, and some potential risk factors such as partial AZFc deletions/duplications and AR CAG repeats [8]. This multiplex QF-PCR analysis was shown to be a rapid, simple, reliable and inexpensive method that can be used as a first-step genetic analysis in infertile patients. Recently, we presented a modified system, where we have included additional markers in the AZFa and AZFb region, as well as a marker for determination of the X/chromosome 3 ratio [13].
Our results showed that Klinefelter’s syndrome and complete AZFc deletions are the most common genetic causes of azoospermia. Partial AZFc deletions as well as AZFc duplications were present in both infertile and fertile men. They may represent a risk factor for male infertility when present on certain Y chromosomal backgrounds.
Gene Polymorphisms and Male Infertility. Analysis of Y chromosome haplogroups, defined by single nucleotide polymorphisms (SNPs), has become a standard approach for studying the origin of human populations and measuring the variability among them. A few groups have studied the possible association of Y chromosome haplogroups with male infertility and Y chromosome microdeletions, but conflicting results have been published. Some recent studies suggested that a Y chromosome background is an important factor that affects partial AZFc deletion formation and its contribution to spermatogenic failure [14].
We have used a hierarchical analysis of 28 SNP markers by multiplex PCR followed by single base extension reactions using a multiplex SNaPshot kit to determine the Y chromosome haplogroups in men from our country [15]. Our initial results showed slight differences in the distribution of the Y chromosome haplogroups such as higher frequency of the R1a haplogroup in infertile patients with a milder phenotype in comparison with those with azoospermia and severe oligozoospermia and fertile controls.
We have studied in detail the Y chromosomal background of different Y chromosome deletions detected in men from our country. Several different Y chromosome haplogroups were determined in men with complete AZFc (b2/b4) deletions and gr/gr deletions. All infertile males with b2/b3 deletion belong to the Hgr E3b1 anomaly, while the only fertile man with this deletion falls within the Hgr N3 anomaly. Most of the men with the b2/b4 duplication, both infertile and fertile, were identified as Hgr R1a, but the frequency of this Hgr was higher in infertile men. There was also a difference in the distribution of the Y chromosome haplogroups in males with the b2/b3 duplication.
The analysis of polymorphisms in genes involved in spermatogenesis represents one of the most exciting areas of research in genetics of male infertility [16]. Polymorphisms in these genes are considered potential risk factors that may contribute to the severity of spermatogenic failure. Polymorphisms in different genes [CAG repeats in AR and DNA polymerase γ (POLG) genes, C677T mutation in 5-methylenetetrahydrofolate reductase (MTHFR), A260G and A386G in the DAZL gene, different polymorphisms in FSHR, ERα, protamine 1 and 2, etc.] have been studied for possible association with male infertility but many of them have presented contradictory results. It is likely that only polymorphisms in association with a specific genetic background and/or with environmental factors can lead to spermatogenic impairment. We have also studied the possible association of several different polymorphisms with male infertility. There was no association between the POLG polymorphism and infertility in Macedonian men [17]. We found a significantly higher percentage of long CAG repeats in patients with mild oligozoospermia indicating the possible association of CAG repeat numbers in exon 1 of the AR gene and mild oligozoospermia [18]. Our preliminary results suggest that there is no association between the MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G polymorphisms and male infertility. Of the nine SNPs evaluated in eight different genes (FASLG, JMJDIA, LOC203413, TEX15, BRDT, OR2W3, INSR and TAS2R38), we found significant association for three SNPs (rs5911500 in the LOC203413, rs3088232 in the BRDT and rs11204546 in the OR2W3 genes, respectively) [19].
Copy number variations (CNVs) represent an important source of genetic diversity with remarkable differences between individuals. Copy number variations can cause spermatogenic failure by their increased number or specific distribution that could result in defective recombination, meiotic failure and loss of germ cells. Copy number variations might also affect the activity of genes important for spermatogenesis. The first study that investigated CNVs in patients with severe oligozoospermia and Sertoly cell only syndrome (SCOS) was published only recently [20]. This study provided a number of candidate genes, possibly causing or being risk factors for, spermatogenic failure. Using array CGH analysis we have also identified several CNVs (UGT2B17 gene on chr4 q13.2; STEAP2 gene on chr7 q21.13; TPTE gene on chr21 p11.2–11.1 and H2BFWT on chrX q22.2) that might be associated with impaired spermatogenesis and male infertility.
136 citations
TL;DR: Direct evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis, and health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.
Abstract: Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.
127 citations
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TL;DR: The presence of not one but three spermatogenesis loci in Yq11 is proposed and that each locus is active during a different phase of male germ cell development.
Abstract: In a large collaborative screening project, 370 men with idiopathic azoospermia or severe oligozoospermia wereanalysed for deletions of 76 DNA loci in Yq11. In 12 individuals, we observed de novo microdeletions involvingseveral DNA loci, while an additional patient had an inherited deletion. They were mapped to three differentsubregions in Yq11. One subregion coincides to the AZF region defined recently in distal Yq11. The second andthird subregion were mapped proximal to it, in proximal and middle Yq11, respectively. The different deletionsobserved were not overlapping but the extension of the deleted Y DNA in each subregion was similar in eachpatient analysed. In testis tissue sections, disruption of spermatogenesis was shown to be at the same phasewhen the microdeletion occurred in the same Yq11 subregion but at a different phase when the microdeletionoccurred in a different Yq11 subregion. Therefore, we propose the presence of not one but three spermatogenesisloci in Yq11 and that each locus is active during a different phase of male germ cell development. As the mostsevere phenotype after deletion of each locus is azoospermia, we designated them as: AZFa, AZFb and AZFc.Their probable phase of function in human spermatogenesis and candidate genes involved will be discussed. INTRODUCTIONGenes for male germ cell development are present on the Ychromosome in different species groups (1–3). In men, theposition of a spermatogenesis locus was mapped in theeuchromatic part of the long Y arm (Yq11). It was called‘azoospermia factor’ (AZF), as the first six men observed withterminal deletions in Yq were azoospermic (4). Mature spermcells were not detectable in their seminal fluid. In all cases, the Ydeletions included the large heterochromatin block of the long Yarm (Yq12) and an undefined amount of the adjacent euchromatin(Yq11). Subsequently, the presence of AZF in Yq11 wasconfirmed by numerous studies at both cytogenetic (5) andmolecular level (6–8). However, the genetic complexity of AZFcould not be revealed by these analyses.This first became possible by the detection of sterile patientswith small interstitial deletions (i.e. microdeletions) in Yq11. Ina study with 13 sterile men suffering from idiopathic azoospermiatwo different microdeletions in Yq11 were observed (9). Theywere mapped to two non overlapping positions in Yq11 interval6 (10). However, further studies of Yq11 microdeletionsassociated to the phenotype of male sterility, only confirmed theposition of an AZF locus in distal Yq11 (11,12). The mostextensive study was performed by Reijo et al. (13) on 89 sterile
1,246 citations
TL;DR: The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein, and the possibility that DAZ is AZF should now be explored.
Abstract: We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.
1,133 citations
972 citations
TL;DR: It is suggested that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
Abstract: A deletion of the Y chromosome at the distal portion of band q11 was found in 6 men with normal male habitus but with azoospermia. Five of them were found during a survey of 1170 subfertile males while the sixth was karyotyped because of slight bone abnormalities. These findings, together with a review of the literature, suggest that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
926 citations
TL;DR: It is shown that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility, and roles for InSl3 in the development of the urogenital tract and in female fertility are revealed.
Abstract: Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.
683 citations