Anomalies génétiques et infertilité masculine

Fifteen percent of couples are infertile and in about 50% of cases the cause is of male origin. The aetiology is still unknown in more than 90% of cases and there may be genetic or environmental causes. Three approaches are used to detect genetic causes for male infertility: 1) cytogenetics, resulting in particular from progress made in molecular cytogenetics and the direct analysis of gametes by in situ molecular hybridation techniques. When a chromosome anomaly, the most common cause of infertility, including deletion of the Y chromosome, is discovered, it is not easy to distinguish between gene anomalies resulting from change and mechanical anomalies that are an integral part of meiosis; 2) the analysis of candidate genes, which often uses data obtained from animal, usually murine, models. This approach, frequently described in the literature, tends to be lengthy, expensive and rarely results in the discovery of an abnormal gene, as is the case, for example, with meiotic genes; 3) Mendel’s approach is clearly the preferred choice, studying as it does cases of inherited infertility, which is much more widespread than we might think.     

L’infertilité masculine: Nos connaissances ne doivent pas faire oublier notre ignorance

About 15% of couples worldwide are affected by reduced fertility. In 20% of cases of couple infertility, the problem can be predominantly attributed to the male. In 20% of cases, a genetic cause of male infertility can usually be identified. The main genetic causes are: autosomal and sex chromosomal abnormalities, microdeletions within regions of the Y-chromosome containing candidate gene families for spermatogenesis and mutations in theCFTR gene. However, despite enormous progress in the understanding of human reproductive physiology, the underlying cause of male infertility often cannot be elucidated. Candidate gene strategies, linkage analysis in large familial forms of male infertility, targeted mutagenesis in the mouse and studies of chromatin reorganization during spermatid maturation should provide rapid progress in our understanding of the genetic factors that contribute to male infertility, which may open up new approaches to the treatment of this condition.     

Autosomal mutations and human spermatogenic failure

Infertility, defined as the inability to conceive after 1 year of unprotected intercourse, is a healthcare problem that has a worldwide impact. Male factors are involved in at least half of these cases of infertility. Despite 33 years of assisted reproductive activities, a considerable number of cases (25–30%) remain idiopathic. This situation can be explained by a poor understanding of the basic mechanisms driving male and female gametogenesis. Compared to multi-organ pathologies, only a few non-syndromic genetic causes of human infertility have been described so far, despite the fact that it is estimated that some infertility cases could be explained by genetic causes and that over 200 infertile or subfertile genetic mouse models have been described. So far, very little has been discovered in the field of human male reproductive genetics. Consequently, genetic tests proposed to infertile couples are limited, although worldwide efforts devoted to the field of human genetics of infertility are expected to provide new genetic tests in the near future. We present the requirements for performing informative genetics studies in the field of infertility, the techniques used and the results obtained so far. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.     

Counteracting effects of heavy metals and antioxidants on male fertility

Infertility is regarded as a global health problem affecting 8–12% of couples. Male factors are regarded as the main cause of infertility in 40% of infertile couples and contribute to this condition in combination with female factors in another 20% of cases. Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Several studies have shown the deteriorative impact of heavy metals on sperm parameters and fertility in human subjects or animal models. Other studies have pointed to the role of antioxidants in counteracting the detrimental effects of heavy metals. In the currents study, we summarize the main outcomes of studies that assessed the counteracting impacts of heavy metal and antioxidants on male fertility. Based on the provided data from animal studies, it seems rational to administrate appropriate antioxidants in persons who suffer from abnormal sperm parameters and infertility due to exposure to toxic elements. Yet, further human studies are needed to approve the beneficial effects of these antioxidants.

     

Assessment of fertility and infertility in boron-exposed Turkish subpopulations: 3. Evaluation of fertility among sibs and in "borate families"

As a part of a work to reveal the health effects of boron and its compounds, fertility and infertility states of sibs of probands, contacted and interviewed in the field, and of their spouses were given. The purposes were to prevent duplications seemingly inevitable in a relatively small community with prevailing consanguinity while analyzing marriages over respective generations and to reveal if there occurred an aggregation of infertile couples. Any family without offspring after about the second year of marriage was considered primary infertile as adopted throughout the study and such families were ascertained through the individual pedigree charts set up according to the instructions of the proband, he (she) himself (herself) being excluded. The rates of childless families of this type were 0.0–3.4% among male and 0.9–3.8% among female sibs of the participant, and 2.3–10.0% among male and 0.0–5.6% among female sibs of his (her) spouse with averages of 2.3% of 1589, 2.6% of 1589, 4.0% of 1314, and 3.3% of 1436 instances, respectively. The differences were insignificant and the rates were not different from those concerning probands themselves and that of a comparable segment of the Turkish population. “Borate families/kindreds” with two or more members engaged in the borate industry were also assessed in order to detect if there was a significant clustering of infertiles within the kindred. Although it was difficult to compare with a matched group, few couples were examples of familial concentration of infertility. These results provided further support that boron exposure does not affect human reproduction primarily and most probably secondarily. This work was partly presented to the 10th International Symposium on Trace Elements in Man and in Animal (TEMA-10), Evian, France, May 2–7, 1999.     

Cell-free and intracellular nucleic acids: new non-invasive biomarkers to explore male infertility

Male infertility is a devastating problem that affects many couples worldwide. However, the molecular mechanisms and causes of idiopathic male infertility remain unclear. Circulating cell-free nucleic acids have an important role in human physiology and emerging evidence suggests that they play a role in male infertility. This review summarizes recent results on cell-free and intracellular nucleic acids in male infertility and discusses their potential use as biomarkers of male infertility in the clinical practice.     

Use of Xenopus laevis frog egg extract in diagnosing human male unexplained infertility.

Approximately one in six married couples find themselves involuntarily infertile. This ratio translates to between two and four million U.S. couples. Although numerous tests are available for diagnosing infertility problems, 5-10 percent of all couples who seek medical treatment are diagnosed with unexplained infertility. Several tests are presently available for diagnosing male infertility; however, none of the present procedures test for activation of the sperm nucleus following entry into the fertilized egg, a series of events critical for the entry of the zygote into the developmental program. We have developed an in vitro human sperm activation assay, using Xenopus laevis frog egg extract. When normal human sperm is permeabilized and then mixed with frog egg extract, the sperm nuclei decondense, synthesize DNA, and recondense during a three-hour time course. We have tested this assay's utility in diagnosing previously unexplained infertility. We found that 20 percent of the male infertility patients produced sperm that responded abnormally in the assay (95 percent confidence interval, 4-48 percent; n = 15), while sperm samples from 15 fertile males showed no abnormal responses (p = 0.0112). These preliminary results indicate that the human sperm activation assay may be a useful tool for diagnosing some cases of human infertility.     

Routine diagnostic testing of Y chromosome deletions in male infertile and subfertile

Male factor infertility elucidated about half the couple of infertility and in around 50% of cases, its etiology remains unknown. The aim of this study was to investigate a predisposing genetic background for Yq deletions and male infertility and effectiveness of molecular genetic approaches have uncovered several etiopathogenetic factors, such as microdeletions of Yq chromosome. The Y chromosome microdeletions removing the azoospermia factor (AZF) regions, which are most common molecular genetic causes of oligospermia or azoospermia. However, with the analysis of Yq deletions, we are able to obtain a better understanding of the clinical significance of genetic anomaly and to the identifying of fertility candidate genes in the AZF regions. Molecular genetic approaches, becomes a routine diagnostic test, that provides an etiology for spermatogenic disturbances, and prognosis for testicular sperm retrieval according to the type of deletion.     

Phosphotyrosine recognition domains: the typical, the atypical and the versatile

Infertility affects one in seven couples globally and has recently been classified as a disease by the World Health Organisation (WHO). While in-vitro fertilisation (IVF) offers effective treatment for many infertile couples, cases exhibiting severe male infertility (19?C57%) often remain difficult, if not impossible to treat. In such cases, intracytoplasmic sperm injection (ICSI), a technique in which a single sperm is microinjected into the oocyte, is implemented. However, 1?C5% of ICSI cycles still fail to fertilise, affecting over 1000 couples per year in the UK alone. Pregnancy and delivery rates for IVF and ICSI rarely exceed 30% and 23% respectively. It is therefore imperative that Assisted Reproductive Technology (ART) protocols are constantly modified by associated research programmes, in order to provide patients with the best chances of conception. Prior to fertilisation, mature oocytes are arrested in the metaphase stage of the second meiotic division (MII), which must be alleviated to allow the cell cycle, and subsequent embryogenesis, to proceed. Alleviation occurs through a series of concurrent events, collectively termed ??oocyte activation??. In mammals, oocytes are activated by a series of intracellular calcium (Ca²⁺) oscillations following gamete fusion. Recent evidence implicates a sperm-specific phospholipase C, PLCzeta (PLC??), introduced into the oocyte following membrane fusion as the factor responsible. This review summarises our current understanding of oocyte activation failure in human males, and describes recent advances in our knowledge linking certain cases of male infertility with defects in PLC?? expression and activity. Systematic literature searches were performed using PubMed and the ISI-Web of Knowledge. Databases compiled by the United Nations and World Health Organisation databases (UNWHO), and the Human Fertilization and Embryology Authority (HFEA) were also scrutinised. It is clear that PLC?? plays a fundamental role in the activation of mammalian oocytes, and that genetic, molecular, or biochemical perturbation of this key enzyme is strongly linked to human infertility where oocyte activation is deficient. Consequently, there is significant scope for our understanding of PLC?? to be translated to the ART clinic, both as a novel therapeutic agent with which to rescue oocyte activation deficiency (OAD), or as a prognostic/diagnostic biomarker of oocyte activation ability in target sperm samples.     

Les molécules de signalisation dans la physiologie et la pathologie testiculaire

Infertility affects an estimated 10% of couples, and in roughly half of these cases the defect can be traced to the men. Male infertility can be due to a failure of spermatogenesis (non-obstructive azoospermia) or to an obstruction (obstructive azoospermia) on deferent ducts. Non-obstructive azoospermia affect about 2% of men, they are due to a failure in spermatogenic maturation. The cause of these defects are still unclear, however, differents causes have been pointed out: genetic defect (Klinefelter syndrome, chromosome Y deletion), physical (irradiation), chemical or infectious affections. But in 40 to 60% of the cases, the cause of non-obstructive azoospermia is not determined. During the last years, from fundamental research, it was hypothezised that an alteration in extracellular signaling systems could potentially caused male infertility. Genetic manipulations show that knock-out or overexpression of some gonadic factors affect spermatogenesis (spermatogenic arrest or tumor formation), for example the systems TGFβ and SCF/c-kit. Experimental data obtained fromin vitro andin vivo approaches show that intratesticular signaling molecules regulate gonadic fonctions with hormones (LH/testosterone, FSH). These local factors might regulate testicular development in the fetal period with the genes of development. Moreover, through adulthood, these local factors could regulate spermatogenesis as a relay of the hormonal action in the testis. Finally, recent studies suggest that abnormalities in local factor expression could lead to testicular pathologies. Futur studies would certainly confirm the important role of signaling molecules in human testicular pathology.     

Oocyte activation and phospholipase C zeta (PLCζ): diagnostic and therapeutic implications for assisted reproductive technology

ABSTRACT: Infertility affects one in seven couples globally and has recently been classified as a disease by the World Health Organisation (WHO). While in-vitro fertilisation (IVF) offers effective treatment for many infertile couples, cases exhibiting severe male infertility (19-57%) often remain difficult, if not impossible to treat. In such cases, intracytoplasmic sperm injection (ICSI), a technique in which a single sperm is microinjected into the oocyte, is implemented. However, 1-5% of ICSI cycles still fail to fertilise, affecting over 1000 couples per year in the UK alone. Pregnancy and delivery rates for IVF and ICSI rarely exceed 30% and 23% respectively. It is therefore imperative that Assisted Reproductive Technology (ART) protocols are constantly modified by associated research programmes, in order to provide patients with the best chances of conception. Prior to fertilisation, mature oocytes are arrested in the metaphase stage of the second meiotic division (MII), which must be alleviated to allow the cell cycle, and subsequent embryogenesis, to proceed. Alleviation occurs through a series of concurrent events, collectively termed 'oocyte activation'. In mammals, oocytes are activated by a series of intracellular calcium (Ca2+) oscillations following gamete fusion. Recent evidence implicates a sperm-specific phospholipase C, PLCzeta (PLCζ), introduced into the oocyte following membrane fusion as the factor responsible. This review summarises our current understanding of oocyte activation failure in human males, and describes recent advances in our knowledge linking certain cases of male infertility with defects in PLCζ expression and activity. Systematic literature searches were performed using PubMed and the ISI-Web of Knowledge. Databases compiled by the United Nations and World Health Organisation databases (UNWHO), and the Human Fertilization and Embryology Authority (HFEA) were also scrutinised. It is clear that PLCζ plays a fundamental role in the activation of mammalian oocytes, and that genetic, molecular, or biochemical perturbation of this key enzyme is strongly linked to human infertility where oocyte activation is deficient. Consequently, there is significant scope for our understanding of PLCζ to be translated to the ART clinic, both as a novel therapeutic agent with which to rescue oocyte activation deficiency (OAD), or as a prognostic/diagnostic biomarker of oocyte activation ability in target sperm samples.     

Sperm centriole assessment identifies male factor infertility in couples with unexplained infertility – a pilot study

Unexplained infertility affects about one-third of infertile couples and is defined as the failure to identify the cause of infertility despite extensive evaluation of the male and female partners. Therefore, there is a need for a multiparametric approach to study sperm function. Recently, we developed a Fluorescence-Based Ratiometric Analysis of Sperm Centrioles (FRAC) assay to determine sperm centriole quality. Here, we perform a pilot study of sperm from 10 fertile men and 10 men in couples with unexplained infertility, using three centriolar biomarkers measured at three sperm locations from two sperm fractions, representing high and low sperm quality. We found that FRAC can identify men from couples with unexplained infertility as the likely source of infertility. Higher quality fractions from 10 fertile individuals were the reference population. All 180 studied FRAC values in the 10 fertile individuals fell within the reference population range. Eleven of the 180 studied FRAC values in the 10 infertile patients were outliers beyond the 95% confidence intervals (P = 0.0008). Three men with unexplained infertility had outlier FRAC values in their higher quality sperm fraction, while four had outlier FRAC values in their lower quality sperm fraction (3/10 and 4/10, P = 0.060 and P = 0.025, respectively), suggesting that these four individuals are infertile due, in part, to centriolar defects. We propose that a larger scale study should be performed to determine the ability of FRAC to identify male factor infertility and its potential contribution to sperm multiparametric analysis.     

The Use of In Vitro Fertilization in the Management of Male Infertility: What the Urologist Needs to Know

Infertility affects approximately 10% to 20% of reproductive-age couples, many of whom may present initially to a urologist. Some couples may be treated medically to increase spontaneous conception rates; however, many will require more aggressive management with in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). IVF involves ovarian stimulation, oocyte retrieval, and fertilization outside of the body; ICSI involves injecting one sperm into the oocyte to promote fertilization. Here we provide a brief overview of IVF and ICSI along with a discussion of the risks involved to facilitate the counseling and care of the infertile couple.Key words: Intracytoplasmic sperm injection, Male infertilityInfertility, defined as the inability to conceive within 12 months of unprotected intercourse, affects approximately 10% to 20% of reproductive-age couples.¹ As couples defer childbearing until later ages and as the obesity epidemic grows, the incidence of infertility is likely to continue to rise.^2,3 Male factor infertility is estimated to contribute to two-thirds of all cases. Of men seeking care for infertility, 18.1% reported being diagnosed with male factor infertility and 13.7% with a sperm or semen problem.⁴The evaluation for male infertility includes a thorough history and physical examination, and the mainstay of diagnostic testing continues to be the semen analysis. If abnormalities are noted on semen analysis, further testing is warranted to evaluate for possible etiologies. Where applicable, treatment is initiated with the goal of improving semen quality and male fertility. Previously, in cases in which semen quality remained profoundly impaired, the successful treatment for male factor infertility was once limited to donor insemination.The development of in vitro fertilization (IVF) revolutionized the management of female infertility. As powerful a tool as this proved to be, however, IVF fertilization rates remained poor in the presence of compromised semen parameters. A significant breakthrough in the treatment of severe male infertility was the development of intracytoplasmic sperm injection (ICSI) in 1992.⁵ By allowing the injection of a single sperm into each oocyte, ICSI provides the possibility of genetic offspring to men who have very scant numbers of motile sperm on semen analysis or who require surgical harvesting.From its inception, assisted reproduction has involved a gynecologist and an embryologist. The urologist is a critical collaborator for the treatment of couples with male factor infertility. Sperm harvested by microsurgical epididymal sperm aspiration, testicular sperm aspiration, or biopsy can be used to fertilize harvested oocytes by ICSI. The urologist may be the first to evaluate a couple for infertility, and will certainly be involved if sperm harvesting is indicated. Therefore, this article reviews the process of assisted reproduction by IVF/ICSI for urologists who may be seeing patients with infertility issues.     

Aquaporins and (in)fertility: More than just water transport

Aquaporins (AQPs) are a family of channel proteins that facilitate the transport of water and small solutes across biological membranes. They are widely distributed throughout the organism, having a number of key functions, some of them unexpected, both in health and disease. Among the various diseases in which AQPs are involved, infertility has been overlooked. According to the World Health Organization (WHO) infertility is a global public health problem with one third of the couples suffering from subfertility or even infertility due to male or female factors alone or combined. Thus, there is an urgent need to unveil the molecular mechanisms that control gametes production, maturation and fertilization-related events, to more specifically determine infertility causes. In addition, as more couples seek for fertility treatment through assisted reproductive technologies (ART), it is pivotal to understand how these techniques can be improved. AQPs are heterogeneously expressed throughout the male and female reproductive tracts, highlighting a possible regulatory role for these proteins in conception. In fact, their function, far beyond water transport, highlights potential intervention points to enhance ART. In this review we discuss AQPs distribution and structural organization, functions, and modulation throughout the male and female reproductive tracts and their relevance to the reproductive success. We also highlight the most recent advances and research trends regarding how the different AQPs are involved and regulated in specific mechanisms underlying (in)fertility. Finally, we discuss the involvement of AQPs in ART-related processes and how their handling can lead to improvement of infertility treatment.     

Lifestyle and fertility: the influence of stress and quality of life on male fertility

Background

Male infertility is a widespread condition among couples. In about 50% of cases, couple infertility is attributable to the male partner, mainly due to a failure in spermatogenesis. In recent times, the crucial role that modifiable lifestyle factors play in the development of infertility have generated a growing interest in this field of study, i.e. aging, psychological stress, nutrition, physical activity, caffeine, high scrotal temperature, hot water, mobile telephone use. Several studies have investigated associations between semen quality and the presence of lifestyle stressors i.e. occupational, life events (war, earthquake, etc.) or couple infertility; overall, these studies provide evidence that semen quality is impaired by psychological stress. In this review, we will discuss the impact of quality of life (modifiable lifestyle factors) and psychological stress on male fertility. In addition, the role that increased scrotal temperature along with inappropriate nutritional and physical exercise attitudes exert on male fertility will be presented.

Conclusion

The decline of male fertility, particularly associated with advancing age, incorrect lifestyles and environmental factors plays an important role on natality, and its consequences on the future on human population makes this an important public health issue in this century. Thus, modification of lifestyle through a structured program of educational, environmental, nutritional/physical exercise and psychological support, combined with the use of nutraceutical antioxidants can prevent infertility and therefore, may help couples to obtain better quality of life and improved possibility to conceive spontaneously or optimize their chances of conception.

     

Detection of Y chromosome microdeletions and mitochondrial DNA mutations in male infertility patients

Infertility affects about 10-15% of all couples attempting pregnancy with infertility attributed to the male partner in approximately half of the cases. Proposed causes of male infertility include sperm motility disturbances, Y chromosome microdeletions, chromosomal abnormalities, single gene mutations, and sperm mitochondrial DNA (mtDNA) rearrangements. To investigate the etiology of decreased sperm fertility and motility of sperm and to develop an appropriate therapeutic strategy, the molecular basis of these defects must be elucidated. In this study, we aimed to reveal the relationships between the genetic factors including sperm mtDNA mutations, Y chromosome microdeletions, and sperm parameters that can be regarded as candidate factors for male infertility. Thirty men with a history of infertility and 30 fertile men were recruited to the study. Y chromosome microdeletions were analyzed by multiplex PCR. Mitochondrial genes ATPase6, Cytb, and ND1, were amplified by PCR and then analyzed by direct sequencing. No Y chromosome microdeletions were detected in either group. However, a total of 38 different nucleotide substitutions were identified in the examined mitochondrial genes in both groups, all of which are statistically non-significant. Fifteen substitutions caused an amino acid change and 12 were considered novel mutations. As a conclusion, mtDNA mutations and Y chromosome microdeletions in male infertility should be examined in larger numbers in order to clarify the effect of genetic factors.     

Genetics of male infertility: the new players

Approximately 10-15% of couples experience infertility and male factors contribute to half of these cases. It was usually thought that infertility cannot be transmitted, but accumulating evidence indicates that many cases are indeed caused by genetic defects, some inherited. The use of single nucleotide polymorphisms (SNP) arrays allowing to genotype the totality of the genome recently led to identify several genes which, when mutated, generate specific infertility phenotypes. With the tremendous progresses in high throughput sequencing techniques, we can expect many more new genes involved in fertility to be identified in the next years. For the patients concerned, these findings mean the possibility of an accurate diagnosis and improved prognosis. Furthermore, these data will lead to a better understanding of the molecular mechanisms underlying spermatogenesis and thus should contribute to identify and offer new therapeutic strategies for the treatment of infertility.     

Choline dehydrogenase polymorphism rs12676 is a functional variation and is associated with changes in human sperm cell function

Approximately 15% of couples are affected by infertility and up to half of these cases arise from male factor infertility. Unidentified genetic aberrations such as chromosomal deletions, translocations and single nucleotide polymorphisms (SNPs) may be the underlying cause of many cases of idiopathic male infertility. Deletion of the choline dehydrogenase (Chdh) gene in mice results in decreased male fertility due to diminished sperm motility; sperm from Chdh(-/-) males have decreased ATP concentrations likely stemming from abnormal sperm mitochondrial morphology and function in these cells. Several SNPs have been identified in the human CHDH gene that may result in altered CHDH enzymatic activity. rs12676 (G233T), a non-synonymous SNP located in the CHDH coding region, is associated with increased susceptibility to dietary choline deficiency and risk of breast cancer. We now report evidence that this SNP is also associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm. Sperm produced by men who are GT or TT for rs12676 have 40% and 73% lower ATP concentrations, respectively, in their sperm. rs12676 is associated with decreased CHDH protein in sperm and hepatocytes. A second SNP located in the coding region of IL17BR, rs1025689, is linked to altered sperm motility characteristics and changes in choline metabolite concentrations in sperm.     

Sacred Conceptions: Clinical Theodicies, Uncertain Science, And Technologies Of Procreation In India

This article argues that the rapid transfer of assisted conception technologies, such as in vitro fertilization, to India is not restricted merely to the modalities of offering potential biomedical resolution of infertility but includes, more crucially, how clinicians and infertile consumers assimilate the “Western technoscience” of conception. The article draws on a larger multisite ethnographic study of infertility and assisted conception in India’s five major cities and is principally based on narratives of clinicians and infertile couples and on clinic-based ethnographic observations. In this article I contend that the success or failure of assisted conception, when situated in the universe of Hindu faith, becomes a powerful critique of the “incompleteness” of the “Western” science of conception. Situating this contention in the broader context of a clinician’s faith, I assert that assisted conception—by conjoining seemingly disparate domains of the traditional and the modern, the sacred and the profane, the human and the superhuman, science and religion—produces clinical theodicies that help explain and contain the tentativeness permeating the conception technologies. The article concludes by arguing that this enchanted version of a thoroughly disenchanted worldview of biomedicine is part of a larger cultural process of indigenization of biomedicine in India.