The most recent estimates indicate that infertility globally affects about 70 million people. More specifically, the current data suggest that one in tem couples at reproductive age is infertile. A set of studies has shown that the causes of infertility are distributed equally over the two sexes, with the percentage of couples with infertility due to the male factor being similar to that of the female factor. Over the years, however, there has been a tendency towards an increase in the contribution of male infertility, a phenomenon that has aroused increasing interest by the scientific community.
In general, male reproductive capacity depends on the correct functioning of four functional groups: spermatogenesis (the process of production and maturing of spermatozoids), endocrine regulation, immunological tolerance and copulation / ejaculatory capacity. Alterations in one or more of these functional groups have a more or less serious impact on the fertile potency of the male. In this particular aspect, anomalies in spermatogenesis stand out as the most common factor within infertility due to male causes.
In the vast majority of cases of altered spermatogenesis, the identification of the mechanisms responsible for the disruption is extremely complex. Nevertheless, this exercise is of great importance not only for better clinical advice to the patient, but also for the development of future therapeutic strategies. Despite the importance of the environmental aspects for the success of spermatogenesis, i tis considered that deregulation of this process is largely a consequence of genetic alterations. Indeed, it is estimated that 15% to 30& of all cases of male infertility are the result of disturbances in the genetic component.
In this field, the Institute of Histology and Development Biology of the Faculty of Medicine of the University of Lisbon (FMUL) and the Institute of Molecular Medicine (IMM) have established partnership agreements with the Multidisciplinary Unit of Human Reproduction of the Santa Maria Hospital (HSM) and with the Dr Ricardo Jorge National Health Institute, with the aim of developing new experimental approaches in the field of genetics of male infertility. These partnerships have been profitable and have allowed the identifying of new factors necessary towards the correct modulation of the male fertile potential. More specifically, the studies carried out have been centred on the molecular characterisation of one of the genomic domains that control spermatogenesis: the AZFc region (from “AZoospermia Factor c”) of the Y chromosome.
As shown in the figure, AZFc is located in the long arm of the Y, and contains a total of four gene families (PRY, BPY2, DAZ and CDY1) which control different functions of the process of the forming of the male gamete. As a consequence of its organisation mainly based on repetitive DNA, AZFc is also one of the most stable domains of the human genome, as shown by its high structural variability in the male population. This instability is reflected in the existence of multiple products of illegitimate reproduction of AZFc, with some of them being able to represent risk factors for the success of spermatogenesis. This is the case of complete or partial deletions of AZFc, the first corresponding to one of the most frequent genetic causes of male infertility. Nevertheless, partial deletions in AZFc, besides being extremely common, are associated to a considerable phenotypical diversity, a fact that has been widely discussed in the field of its clinical implications. In fact, these partial deletions had already been detected in a diversified range of spermatogenic profiles that vary from the normal production of spermatozoids to the complete absence of gametes in ejaculation. This variability is also reflected on the level of the final result of the different population screenings that have been carried out, given that they are inconclusive as to the existence or not of an association among partial deletions in AZFc and a tendency to anomalies in spermatogenesis.
In this context, the scientific activity carried out in the FMUL has been a determining factor for the clarification of the functional consequences of the most frequent pattern of partial deletion of AZFc (deletion gr/gr). Indeed, in a partnership with the institutions mentioned above, there has been the development of an extensive programme of screening for partial deletions of AZFc in the Portuguese population, being complemented by a critical and detailed re-assessment of the tests carried out in other parts of the world. This approach has made it possible to conclude that the risk of male infertility associated to gr/gr deletion depends on the evolutions levels of the Y chromosome present in the population. In other words, depending on the haplogroup, that is, on the “evolution type” of the Y chromosome that is inherited by the male progenitor, its deletion may or not represent a risk of infertility. In the case of the Portuguese population, the most prevalent Y chromosome haplogroups in our genetic heritage are in fact associated to this risk, being reflected in an odds ratio of 5.6 (IC 95%: 1.6–30.1) that a man might possess a partial deletion in AZFc and be infertile. These observations, published in the scientific reviews BMC Genomics (in 2007) and Human Reproduction Update (in 2010), allow one to clarify one of the most controversial aspects of reproduction genetics, as well as unifying a set of epidemiological studies that were previously seen as discordant. In addition, the results show the importance of the role played by the modulating factors in genetic information (in this case the Y chromosome haplogroup) for the determining of the phenotype in cases where there are genetic alterations that are predisposed to infertility.
It is exactly in this area, namely in the identification and management of factors modulating genetic risk, that one expects major advances in the biomedical research into infertility. Such advances will allow a progressive personalization of the therapeutics offered to infertile couples, in accordance not only with their genetic constitution, but also with the modulating factors of the expression of that information to which they had been exposed (the epigenetic). Both components will certainly be the driving force for a substantial improvement in the clinical options made available to these couples. It is exactly within this context of major expectations and even greater responsibilities and challenges that the research carried out in the Unit of Reproduction Biology of the Institute of Histology and Development Biology of the FMUL is set.
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A- Drawing of the Y chromosome, with the three domains of regulation of spermatogenesis (AZFa, AZFb and AZFc) indicated above. The euchromatin is represented in blue and the heterochromatin in grey.
B- Genome architecture of the AZFc region. The coloured arrows indicate blocks of repetitive DNA.
C- Genetic content of the AZFc region. Black triangles represent active copies and white triangles represent pseudogenes. Figure taken from Navarro-Costa et al., Human Reproduction Update, 2010
Paulo Navarro-Costa
Institute of Histology and Development Biology,
Faculty of Medicine of the University of Lisbon (FMUL)
navarro-costa@fm.ul.pt
In general, male reproductive capacity depends on the correct functioning of four functional groups: spermatogenesis (the process of production and maturing of spermatozoids), endocrine regulation, immunological tolerance and copulation / ejaculatory capacity. Alterations in one or more of these functional groups have a more or less serious impact on the fertile potency of the male. In this particular aspect, anomalies in spermatogenesis stand out as the most common factor within infertility due to male causes.
In the vast majority of cases of altered spermatogenesis, the identification of the mechanisms responsible for the disruption is extremely complex. Nevertheless, this exercise is of great importance not only for better clinical advice to the patient, but also for the development of future therapeutic strategies. Despite the importance of the environmental aspects for the success of spermatogenesis, i tis considered that deregulation of this process is largely a consequence of genetic alterations. Indeed, it is estimated that 15% to 30& of all cases of male infertility are the result of disturbances in the genetic component.
In this field, the Institute of Histology and Development Biology of the Faculty of Medicine of the University of Lisbon (FMUL) and the Institute of Molecular Medicine (IMM) have established partnership agreements with the Multidisciplinary Unit of Human Reproduction of the Santa Maria Hospital (HSM) and with the Dr Ricardo Jorge National Health Institute, with the aim of developing new experimental approaches in the field of genetics of male infertility. These partnerships have been profitable and have allowed the identifying of new factors necessary towards the correct modulation of the male fertile potential. More specifically, the studies carried out have been centred on the molecular characterisation of one of the genomic domains that control spermatogenesis: the AZFc region (from “AZoospermia Factor c”) of the Y chromosome.
As shown in the figure, AZFc is located in the long arm of the Y, and contains a total of four gene families (PRY, BPY2, DAZ and CDY1) which control different functions of the process of the forming of the male gamete. As a consequence of its organisation mainly based on repetitive DNA, AZFc is also one of the most stable domains of the human genome, as shown by its high structural variability in the male population. This instability is reflected in the existence of multiple products of illegitimate reproduction of AZFc, with some of them being able to represent risk factors for the success of spermatogenesis. This is the case of complete or partial deletions of AZFc, the first corresponding to one of the most frequent genetic causes of male infertility. Nevertheless, partial deletions in AZFc, besides being extremely common, are associated to a considerable phenotypical diversity, a fact that has been widely discussed in the field of its clinical implications. In fact, these partial deletions had already been detected in a diversified range of spermatogenic profiles that vary from the normal production of spermatozoids to the complete absence of gametes in ejaculation. This variability is also reflected on the level of the final result of the different population screenings that have been carried out, given that they are inconclusive as to the existence or not of an association among partial deletions in AZFc and a tendency to anomalies in spermatogenesis.
In this context, the scientific activity carried out in the FMUL has been a determining factor for the clarification of the functional consequences of the most frequent pattern of partial deletion of AZFc (deletion gr/gr). Indeed, in a partnership with the institutions mentioned above, there has been the development of an extensive programme of screening for partial deletions of AZFc in the Portuguese population, being complemented by a critical and detailed re-assessment of the tests carried out in other parts of the world. This approach has made it possible to conclude that the risk of male infertility associated to gr/gr deletion depends on the evolutions levels of the Y chromosome present in the population. In other words, depending on the haplogroup, that is, on the “evolution type” of the Y chromosome that is inherited by the male progenitor, its deletion may or not represent a risk of infertility. In the case of the Portuguese population, the most prevalent Y chromosome haplogroups in our genetic heritage are in fact associated to this risk, being reflected in an odds ratio of 5.6 (IC 95%: 1.6–30.1) that a man might possess a partial deletion in AZFc and be infertile. These observations, published in the scientific reviews BMC Genomics (in 2007) and Human Reproduction Update (in 2010), allow one to clarify one of the most controversial aspects of reproduction genetics, as well as unifying a set of epidemiological studies that were previously seen as discordant. In addition, the results show the importance of the role played by the modulating factors in genetic information (in this case the Y chromosome haplogroup) for the determining of the phenotype in cases where there are genetic alterations that are predisposed to infertility.
It is exactly in this area, namely in the identification and management of factors modulating genetic risk, that one expects major advances in the biomedical research into infertility. Such advances will allow a progressive personalization of the therapeutics offered to infertile couples, in accordance not only with their genetic constitution, but also with the modulating factors of the expression of that information to which they had been exposed (the epigenetic). Both components will certainly be the driving force for a substantial improvement in the clinical options made available to these couples. It is exactly within this context of major expectations and even greater responsibilities and challenges that the research carried out in the Unit of Reproduction Biology of the Institute of Histology and Development Biology of the FMUL is set.
A- Drawing of the Y chromosome, with the three domains of regulation of spermatogenesis (AZFa, AZFb and AZFc) indicated above. The euchromatin is represented in blue and the heterochromatin in grey.
B- Genome architecture of the AZFc region. The coloured arrows indicate blocks of repetitive DNA.
C- Genetic content of the AZFc region. Black triangles represent active copies and white triangles represent pseudogenes. Figure taken from Navarro-Costa et al., Human Reproduction Update, 2010
Paulo Navarro-Costa
Institute of Histology and Development Biology,
Faculty of Medicine of the University of Lisbon (FMUL)
navarro-costa@fm.ul.pt
