Reproduction is required for the survival of all mammalian species, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.

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The biology of infertility: research advances and clinical challenges

https://www.clevelandclinic.org/reproductiveresearchcenter/docs/agradoc344.pdf

The genetic causes of male factor infertility: A review

Male infertility represents one of the clearest examples of a complex disease with a substantial genetic basis. Numerous male mouse models, mutation screening and association studies reported over the last few years reveal the high prevalence of genetic causes of spermatogenic impairment, accounting for 10-15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, but this protective mechanism may be overcome by assisted reproduction techniques. Consequently, the identification of genetic factors is important for appropriate management of the infertile couple. However, a large proportion of infertile males are diagnosed as idiopathic, reflecting poor understanding of the basic mechanisms regulating spermatogenesis and sperm function. Furthermore, the molecular mechanisms underlying spermatogenic damage in cases of genetic infertility (for example Yq microdeletions) are not known. These problems can be addressed only by large scale association studies and testicular or spermatozoal expression studies in well-defined alterations of spermatogenesis. It is conceivable that these studies will have important diagnostic and therapeutic implications in the future. This review discusses the genetic causes of male infertility known to date, the genetic polymorphisms possibly associated with male infertility, and reports novel results of global gene expression profiling of normal human testis by microarray technology.

https://www.rbmojournal.com/article/S1472-6483(10)60677-3/pdf

Male infertility: role of genetic background

The molecular diagnosis of Y-chromosomal microdeletions is a common routine genetic test which is part of the diagnostic workup of azoospermic and severe oligozoospermic men. Since 1999, the European Academy of Andrology (EAA) and the European Molecular Genetics Quality Network (EMQN) have been actively involved in supporting the improvement of the quality of the diagnostic assays by publication of the laboratory guidelines for molecular diagnosis of Y-chromosomal microdeletions and by offering external quality assessment trials. The present revision of the 2004 laboratory guidelines summarizes all the clinical novelties related to the Y chromosome (classic, partial and gene-specific deletions, genotype–phenotype correlations, methodological issues) and provides an update on the results of the quality control programme. These aspects also reflect the consensus of a large group of specialists present at a round table session during the recent Florence-Utah-Symposium on ‘Genetics of male infertility’ (Florence, 19–21 September, 2013). During the last 10 years the gr/gr deletion has been demonstrated as a significant risk factor for impaired sperm production. However, the screening for this deletion type in the routine diagnostic setting is still a debated issue among experts. The original basic protocol based on two multiplex polymerase chain reactions remains fully valid and appropriate for accurate diagnosis of complete AZF deletions and it requires only a minor modification in populations with a specific Y chromosome background. However, in light of novel data on genotype–phenotype correlations, the extension analysis for the AZFa and AZFb deletions is now routinely recommended. Novel methods and kits with excessively high number of markers do not improve the sensitivity of the test, may even complicate the interpretation of the results and are not recommended. Annual participation in an external quality control programme is strongly encouraged. The 12-year experience with the EMQN/EAA scheme has shown a steep decline in diagnostic (genotyping) error rate and a simultaneous improvement on reporting practice.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.2047-2927.2013.00173.x

EAA/EMQN best practice guidelines for molecular diagnosis of Y‐chromosomal microdeletions: state‐of‐the‐art 2013

Well-resolved molecular gene trees illustrate the concept of descent with modification and exhibit the opposing processes of drift and migration, both of which influence population structure. Phylogenies of the maternally inherited mtDNA genome and the paternally inherited portion of the nonrecombining Y chromosome retain sequential records of the accumulation of genetic diversity. Although knowledge regarding the diversity of the entire human genome will be needed to completely characterize human genetic evolution, these uniparentally inherited loci are unique indicators of gender in modulating the extant population structure. We compare and contrast these loci for patterns of continuity and discreteness and discuss how their phylogenetic diversity and progression provide means to disentangle ancient colonization events by pioneering migrants from subsequent overlying migrations. We introduce new results concerning Y chromosome founder haplogroups C, DE, and F that resolve their previous trifurcation and improve the harmony with the mtDNA recapitulation of the out-of-Africa migration.

http://mega.bioanth.cam.ac.uk/pdfs/Underhill2007mtDNAandYAnRevGenet.pdf

Use of Y Chromosome and Mitochondrial DNA Population Structure in Tracing Human Migrations

Genetic causes of male infertility.

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...

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Molecular and Clinical Characterization of Y Chromosome Microdeletions in Infertile Men: A 10-Year Experience in Italy

In women, single nucleotide polymorphisms (SNP) of the FSH receptor ( FSHR ) gene influence FSH concentrations and the sensitivity of the FSHR to FSH in vivo  In contrast, the significance of FSHR R gene SNP in the male is poorly understood To this aim, the possible role of three FSHR SNP was evaluated in male infertility SNP in exon 10 (codon 307 and 680) and in the core promoter region (at position −29) of the FSHR gene were analysed by polymerase chain reaction-restriction fragment length polymorphism technique in 150 men representative of the general population, 107 proven fathers, 92 normozoospermic controls, and 215 infertile patients classified according to sperm parameters (38 azoospermia, 53 severe oligozoospermia, 48 moderate oligozoospermia, and 76 slight oligozoospermia) Reproductive hormones were measured in infertile males and normozoospermic controls No significant difference was found in allelic variants frequency and genotype distribution between each category of subjects when analysing the FSHR exon 10 SNP alone and in combination with the SNP at position −29 Serum FSH concentrations and other andrological parameters did not differ between subjects with different genotype within each group The data showed that in the Italian population, FSHR genotypes have no influence on FSH concentrations both in normal and infertile males and do not associate with spermatogenetic impairment

https://www.rbmojournal.com/article/S1472-6483(10)61026-7/pdf

FSH receptor gene polymorphisms in fertile and infertile Italian men

Insulin-like factor 3 (INSL3) is expressed in Leydig cells of the testis and theca cells of the ovary. This peptide affects testicular descent by acting on gubernaculum via its specific receptor leucine-rich repeat-containing G proteincoupled receptor 8 (LGR8). From initial animal data showing the cryptorchid phenotype of Insl3/ Lgr8 mutants, an extensive search for mutations in INSL3 and LGR8 genes was undertaken in human patients with cryptorchidism, and a frequency of mutation of 4–5% has been detected. However, definitive proofs of a causative role for some of these mutations are still lacking. More recent data suggest additional paracrine (in the testis and ovary) and endocrine actions of INSL3 in adults. INSL3 circulates at high concentrations in serum of adult males and its production is dependent on the differentiation effect of LH. Therefore, INSL3 is increasingly used as a specific marker of Leydig cell differentiation and function.

Paracrine and endocrine roles of insulin-like factor 3.

Background: A limited number of studies aimed at investigating the possible association of Y-chromosome haplogroups with microdeletions of the azoospermia factors (AZFs) or with particular infertile phenotypes, but definitive conclusions have not been attained. The main confounding elements in these association studies are the small sample sizes and the lack of homogeneity in the geographical origin of studied populations, affecting, respectively, the statistical power and the haplogroup distribution.

Materials and methods: To assess whether some Y-chromosome haplogroups are predisposing to, or protecting against, azoospermia factor c (AZFc; b2/b4) deletions, 31 north Italian patients carrying the AZFc b2/b4 microdeletion were characterised for 8 Y-chromosome haplogroups, and compared with the haplogroup frequency shown by a north Italian population without the microdeletion (n = 93).

Results and discussion: A significant difference was observed between the two populations, patients with microdeletions showing a higher frequency of the E haplogroup (29.3% vs 9.7%, p<0.01). The geographical homogeneity of the microdeleted samples and of the control population, controlled at microgeographical level, allows the possibility that the geographical structure of the Y genetic variability has affected our results to be excluded.

Conclusion: Thus, it is concluded that in the north Italian population Y-chromosome background affects the occurrence of AZFc b2/b4 deletions.

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Barbara Arredi

Papers

Genetic causes of male infertility.

Molecular and Clinical Characterization of Y Chromosome Microdeletions in Infertile Men: A 10-Year Experience in Italy

FSH receptor gene polymorphisms in fertile and infertile Italian men

Paracrine and endocrine roles of insulin-like factor 3.

Y-chromosome haplogroups and susceptibility to azoospermia factor c microdeletion in an Italian population