[Frontiers In Bioscience, Scholar, 9, 448-508, June 1, 2017]

Genomics: Tool to predict and prevent male infertility

Ashutosh Halder1, Prashant Kumar1, Manish Jain1, Amanpreet Kaur Kalsi1

1Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Genetic causes of male infertility
3.1. Testicular failure
3.2. Pre-testicular failure
3.3. Post-testicular failure
4. Copy number variations (CNVs) with male infertility
5. Epigenetic modification in male gametogenesis and male infertility
6. Evaluation
7. Management
8. Importance of exploring genetic basis of male infertility
9. How to predict and prevent male infertility using genomics?
10. Acknowledgments
11. References

1. ABSTRACT:

A large number of human diseases arise as a result of genetic abnormalities. With the advent of improved molecular biology techniques, the genetic etiology of male infertility is increasing. The common genetic factors responsible for male infertility are chromosomal abnormalities, Yq microdeletion and cystic fibrosis. These are responsible for approximately 30 percent cases of male infertility. About 40 percent cases of male infertility are categorized as idiopathic. These cases may be associated with genetic and genomic abnormalities. During last few years more and more genes are implicated in male infertility leading to decline in prevalence of idiopathic etiology. In this review we will summarize up to date published works on genetic etiologies of male infertility including our own works. We also briefly describe reproductive technologies used to overcome male infertility, dangers of transmitting genetic disorders to offspring and ways to prevent transmission of genetic disorders during assisted reproduction. At the end we will provide our points on how genomic information can be utilized for prediction and prevention of male infertility in coming years.

2. INTRODUCTION

Infertility is defined as the failure to achieve conception even after 12 months of regular unprotected sexual intercourse. Infertility affects approximately 10-15% of couples in their reproductive age (1). Male infertility is as prevalent as female infertility and contributes about 50% cases (2). The incidence of male infertility over the years is rising. Male infertility could result from disorders of hormonal control (pre-testicular) or spermatogenesis (testicular) or sperm transport, epididymal maturation & fertilization (post-testicular). The majority (over 85%) of cases of male infertility are testicular origin. The genetic etiology accounts for up to 30% of cases until recently (3). Still, most cases of male infertility are thought to be idiopathic (4) which may actually be linked to unknown genetic/ genomic abnormalities.

Genetics play important role in the causation of human disease. Genetics affect male infertility by influencing hormonal homeostasis (mostly pre testicular causes), spermatogenesis (testicular causes) and sperm quality & quantity (testicular and post testicular causes). The genetic basis of infertility can result from chromosomal abnormalities, Yq microdeletion/azoospermia factor (AZF) deletion, copy number variations (CNVs), monogenic, multifactorial, mitochondrial and epigenetic abnormalities. Some of the likely CNV hot spots reported for testis expressed genes are 1p31-33, 6p21, 6p22.1, Xq28, 7q31, 3p21.1, etc (5). Although mitochondrial mutations in sperm decrease sperm motility, in general, it does not impair fertility (6). Epigenetic changes in spermatozoa are very critical for normal fertilization and embryonic development. Hypermethylation of promoters of genes like MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, SNRPN, etc are implicated with male infertility (7). Monogenic disorders like cystic fibrosis mutation leading to congenital absence of vas deferens (CAVD) can present as obstructive azoospermia. Other abnormalities that could lead to male infertility are sperm chromosome abnormality (8), sperm DNA instability, etc. Infertile male with oligo/ astheno/ teratozoospermia (with normal blood karyotype) have three-fold increase in chromosomal abnormalities in sperms (9).

With the advent of improved molecular biology techniques, the genetic basis of disease is coming up with an increasing number of disorders. This is also observed with male infertility and is soon going to change previous estimates of genetic contribution to male infertility because large number of gene are expressed in the male germ cells and their defect is likely to be responsible for the infertility. It is very important to know underlying genetic etiology as this information can be utilized for identifying abnormality before disease onset, predicting prognosis, preventing disease, planning treatment at/before onset of disease as well as predicting health of the offspring.

Understanding genetics of male infertility depends on the development of research in genomics and epigenomics. Research in this field has resulted accumulation of extensive genomics, epigenomics, transcriptomics and proteomics data. In coming years DNA repositories from informative families will help in defining more and more underlying genetic etiologies thus potential future genetic tests. In this review we will review the known genetic causes of male factor infertility along with some new findings of our group that may be relevant in coming days and futuristic use of genomics as part of predictive & preventive reproductive medicine practice.

3. GENETIC CAUSES OF MALE INFERTILITY

Genetic causes of male infertility are chromosomal abnormalities, AZF deletions of Y chromosome, monogenic disorders, polygenic disorders, multifactorial disorders, mitochondrial or epigenetic disorders. The common causes of male infertility are chromosomal disorders (mostly 47,XXY/Klinefelter syndrome) and Yq microdeletions/AZF deletions (10,11). Chromosomal abnormalities and Yq microdeletion account for about 25% of cases of male infertility with azoospermia, suggesting that these two abnormalities are very important genetic etiologies of spermatogenic failure. So, it is essential to screen them during evaluation of male infertility (12). The systemic chromosomal disorders are responsible for approximately 5% of male infertility and about 15% in azoospermia (2). The sex chromosome aneuploidy, in particular Klinefelter syndrome (Figure 1), is the most common chromosomal abnormality detected in male infertility (13). It is seen in one out of every 1000 males. The patient is usually tall and presents with small testes, reduced fertility and gynecomastia. About 50% cases of Klinefelter syndrome are mosaic (Figure 2), where 47,XXY cell line is present along with 46,XX or 46,XY or 48,XXYY or 48,XXXY cell lines or any combinations. The sex chromosomes play a major role in germ cell development in mammals as sex chromosomes contain many genes that are expressed in the gonads. The gonadal defect in 47,XXY (Klinefelter syndrome) patient is mainly due to germ cell survival (10) or germ cell maturation breakdown (14).

Other sex chromosome abnormalities seen with male infertility are 46,XX (15,16) sex reversal male (Figure 3), dicentric Y (Figure 4), etc. The XX male syndrome is a rare genetic disorder. The phenotype is variable; ranging from a severe impairment of the external genitalia to a normal male phenotype with infertility. This syndrome was first described by de la Chapelle et al (17). The 46,XX male syndrome affects 1 in 20000 newborn males (18). In general, SRY-positive 46,XX male individuals present somehow similar to Klinefelter syndrome including normal external male genitalia, soft small testes, gynecomastia, poor facial hair, diminished libido, hypergonadotropic hypogonadism and low testosterone (Figure 3). Testicular histology or cytology with this syndrome is inconsistent; some shows hyalinization of seminiferous tubule with absence of germ cells while others present with Sertoli cell only syndrome (19).

Dicentric Y (Figure 4) is the most frequent structural rearrangement of the Y chromosome. Often centromeres are close to each other and act as monocentric thus replicate as normal chromosome (20). Often one of the centromeres is functionally inactive (21-23). Dicentric Y with longer inter-centromeric distance relies heavily on functional inactivation of one centromere to achieve mitotic stability. In contrast, those with shorter inter-centromeric distance are less dependent upon this mechanism (24). Mitosis may be possible in somatic cells in this case (with longer inter-centromeric distance) presumably because of the cell survival phenomenon through inactivation of one centromere. But in germ cell meiosis requires pseudo autosomal region (PAR) paring and changes of PAR CNVs associated with dicentric Y will lead to meiotic arrest. Spermatogenic failure is reported in cases of Y chromosome structural abnormalities, including dicentric Y chromosome (25). Undisturbed pairing of sex chromosome is an essential condition of correct segregation of the chromosomes during spermatogenesis (26,27). Chromosomal translocations, in particular autosomal are also observed 4–10 times more frequently in infertile males in comparison with normal fertile male (28). Carriers of translocations usually have a normal phenotype but could be infertile if breakpoints involved genes of spermatogenesis (2). Rarely chromosomal abnormality may restrict only to gonads (gonadal mosaicism) and present as infertility in translocation carriers or recurrent chromosomal abnormality in offspring. Moreover, sperm aneuploidy rate is increased in oligospermia, oligo-azoospermia, asthenozoospermia, etc and sperm aneuploidy test should be employed as a routine screening test before intracytoplasmic sperm injection to assess the need for preimplantation/prenatal genetic diagnosis. Sperm aneuploidy assessment is carried out by fluorescence in situ hybridization analysis (FISH) test (Figure 5), as it appears to be valuable and reliable test to study aneuploidy (8,29). Sperm FISH may be helpful for patients with Klinefelter syndrome, structural chromosomal abnormalities, teratospermia in particular macrocephalic, multinucleated and multiflagellate sperm and 46,XY men with nonobstructive azoospermia (before intra cytoplasmic sperm injection/ICSI with epididymal/testicular sperm aspiration). Sperm FISH in these men will aid in counseling and decision making. Higher incidence of aneuploidies, in particular sex chromosome was observed in embryos derived from in vitro fertilization/IVF & ICSI using epididymal or testicular sperm. Hence it is important to include sperm FISH analysis in preliminary tests for infertile couples with repeated IVF failures (30).

The Y chromosome is very important for male sex determination, differentiation and fertility because it contains many genes critical for development of male gonads and spermatogenesis (Table 1). However, human Y chromosome has limited number of genes as compared to other chromosomes. This may have resulted from degeneration process during evolution (31). The genes on Y chromosome are subdivided into two groups. The first group has genes which are expressed ubiquitously, exist as single copy having X homologues and perform housekeeping functions. The second group includes genes that have multiple copies (except SRY) and testes specific expression performing additional specialized functions. The X homologue genes are important as these provide an alternate answer for gene dose compensation. These genes also escape X inactivation and encode for proteins (32).

Spermatogenesis related genes of Y chromosome are located on Yq11.2 region, known as AZF/azoospermia factor region. AZF deletion or Yq microdeletion is frequently observed with male infertility (Figure 6-8). The prevalence of Yq microdeletion/ AZF deletion in azoospermic men ranges from 10%–15% and in oligozoospermic men from 5%–10% (33). The Yq microdeletion/ AZF deletion (0.8–7.7 mb size) is most common identifiable genetic cause of spermatogenic failure (34,35). Most deletions arise de novo indicating unstable nature of the region due to presence of repetitive palindromic DNA sequences (36). Due to high degree of homology between these palindromes intra-chromosomal recombination and rearrangements occur frequently leading to deletions or duplications. AZF genes encode for 27 distinct proteins (37) and have key roles in spermatogenesis, including germ cell cycle regulation and meiosis (38). The AZF is comprised of three sub-regions; AZFa, located on Yq11.21 and AZFb & AZFc, partially overlapping regions, located on Yq11.221 to Yq11.23 (39,40). The size of the AZFa region is over 1Mb whereas of AZFb covers 1-3 Mb and AZFc is about 3.5 Mb. Another region AZFd is located between AZFb and AZFc, but requires more verification (41). The AZFa region (Yq11.21) contains few genes viz., USP9Y, DDX3Y and UTY (32,42,43). USP9Y (ubiquitin specific protease 9; older name Drosophila fat facets related Y) is situated at genomic coordinate Y:12701230-12860843, exists in a single copy and has an X-homologue, which escapes X-inactivation. USP9Y occupies less than half of the AZFa interval (43). DDX3Y (Dead/H Box 3, Y-Linked; older name DBY) is situated at genomic coordinate Y:12903998-12920477, has an X-homologue (DDX3X) on the short arm of the X chromosome and is associated with Sertoli cell-only syndrome or hypospermatogenesis. UTY (ubiquitous TPR motif on the Y) is situated at genomic coordinate Y:13230769-13480669, has an X homologue and is not directly involved with male infertility. Deletion of a single gene (eg, DBY/DDX3Y) or combinations of genes has been associated with spermatogenic disruption, in particular with sertoli cell only syndrome (39) or hypospermatogenesis (43). The AZFb region (Yq11.221-q11.223) contains many genes like CDY2A, CDY2B, PRORY/CYorf17, EIF1AY, HSFY1, HSFY2, PRY, RBMY1A1, RBMY1B, RBMY1D, RBMY1E, RBMY1F, RBMY1J and RPS4Y2. The role of AZFb loss in male infertility can be explained by the involvement of HSFY1 and HSFY2 (heat shock transcription factor, Y-linked 1 and 2) genes. These genes have testis-specific expression and contribute in spermatocyte maturation (44). Deletion or under expression of HSFY is associated with testicular maturation arrest (45,46). RBMY genes are expressed only in the testicular germ cells (47). The AZFc region contains several genes like CDY1B, CYorf17, EIFIAY, PRY, PRY2, RBMY1A1, RBMY1B, RBMY1D, RBMY1E, RBMY1F, RBMY1J, RPS4Y2, BPY2, BPY2B, DAZ1, DAZ2, DAZ3, KDM5D, TTTY3, TTTY4, TTTY6, TTTY17, TSPY1, CSPG4LY, GOLGA2LY, etc. The Yq11.222-q11.223 (AZFbc) has multiple genes like CYorf17 (PRORY), EIF1AY, HSFY2, KDM5D, RPS4Y2, PRY, PRY2 and RBMY family genes (all 6 copies). These are important for spermatogenesis (Gene, GeneCards, OMIM, etc databases). Similarly, Yq11.223 (AZFc) contains PRY, PRY2 and RBMY family genes (6 copies), Yq11.223-q11.23 (AZFc) contains CDY1B gene and Yq11.23 (AZFc) contains CDY1 gene. These genes are important for the spermatogenesis (Gene, GeneCards, Online Mendelian Inheritance in Man/OMIM, etc databases). One of the important genes in AZFc region is DAZ and this gene belongs to a multigene family. Several copies of DAZ gene (with individual variation in copy number) are present in AZFc region (39,48). The gene has structural similarity with RBMY. It is a 42 kb gene comprising 16 exons. Deletion of this gene is associated with spermatogenic defects (49). The AZF region is one of the unstable spot in human genome. The Y chromosome has a unique structure, covered by large palindromes of long, near identical repeats (37). This makes the Y chromosome prone to undergo rearrangements, especially in AZFc region (36) and thus AZF deletion is the leading genetic causes of spermatogenic failure.

The reasons for disruption in spermatogenesis beyond chromosome abnormalities, AZF deletions and CFTR mutations (responsible for congenital bilateral agenesis of vas deference i.e., obstructive azoospermia) remain largely unclear until recently. After full clinical workup, about 30% cases with male infertility are considered idiopathic and an additional 40% have insufficient/uncertain causes (50). On the other hand, it is estimated that about 30% of azoospermia or oligozoospermia are caused by chromosomal abnormalities or mutations or disruption of genes involved in germ cell production and function (51). A large number of genes (approximately 1 in 25 of all mammalian genes) are expressed in the male germline (52) and mutations in these genes could cause male infertility. Mutations of genes that regulate recombination and repair of the genome can lead to meiotic arrest (53). Androgens are required for spermatogenesis and its activity is mediated by the androgen receptor. Androgen receptor variants with resistance to androgen are known to compromise spermatogenesis. Androgen receptor gene also has two trinucleotide (CAG & GGC) polymorphisms with variation in repeat length in the population. The usual range in repeat length of CAG is 9 to 36 repeats (54). Individuals with more than 40 repeats present with reduced virilization, defective spermatogenesis and infertility (55).

Mitochondrial DNA is inherited maternally and found in multiple copies in a cell. Mutated & wild type mitochondrial DNA mixture (heteroplasmy) in varying frequency is observed within cells. Mitochondrial DNA produces disease phenotype if load of the mutated DNA cross a certain threshold, usually over 80%. Mitochondrial DNA (mtDNA) abnormality may influence male fertility, but it is controversial. Abnormal mitochondria can present as defect in sperm motility (56) or sperm dysfunction. During spermiogenesis most cytoplasm and mitochondria are lost and the remaining mitochondria are concentrated around the sperm mid-piece where they are likely to be vital for sperm motility and therefore male fertility. Mitochondrial genes which undergo mutations associated with male infertility are ANT4 (adenine nucleotide transferase 4), IMMPL2 (inner mitochondrial membrane peptidase 2 like), POLG (DNA polymerase subunit gamma), CLPP (caseinolytic mitochondrial matrix peptidase proteolytic subunit), TWNK (twinkle mtDNA helicase), HARS2 (histidyl-tRNA synthetase 2), LARS2 (leucyl-tRNA synthetase 2), AARS2 (alanyl-tRNA synthetase 2), ATPase 6/ATPase 8, TYMP (thymidine phosphorylase), RRMB2 (ribonucleotide reductase regulatory TP53 inducible subunit M2B), etc (57). POLG is involved in the replication of mtDNA. Variations in the CAG repeat numbers of the catalytic subunit of the POLG gene is implicated with male infertility. The ten CAG repeats were found to be the most common allele and absence of these repeats is associated with male infertility (57). However, POLG-CAG repeats variation is not associated with male infertility in Indian population (58).

3.1. Testicular failure

Spermatogenesis is a process of germ cell development and differentiation in seminiferous tubules of the testis. It is characterized by three specific phases: mitosis, meiosis and differentiation involving spermatogonia, spermatocytes and spermatids. Spermatogenesis failure may be primarily due to defect in testes, mostly genetic defects (Table 2) or secondary to acquired pathology. The acquired causes are chemotherapy, radiotherapy, gonadotoxic drugs, vitamin A/zinc deficiencies, chronic liver/kidney failure, infections, endocrinopathy, etc. Other causes are varicocele, cryptorchidism, etc.

Primary testicular failure is a condition where testes fail to produce sperm despite adequate hormonal support and is characterized by high level of gonadotropins, in particular FSH. Primary testicular failure is a major cause of non-obstructive azoospermia and oligospermia. It affects approximately 1% of all men and 10% of those seeking fertility evaluations (59). Primary testicular failure is characterized by interruption of germ cell development and differentiation. There is either an absence of germ cells in testes or presence of germ cells (few or normal numbers) but differentiation into spermatozoa is interrupted or germ cells die prematurely. Most primary testicular failure cases present with hypergonadotropic hypogonadism. Primary testicular failure is classified into four distinct subtypes according to histopathology/ cytology viz., Sertoli Cell Only Syndrome, Maturation Arrest, Hypospermatogenesis and Testicular atrophy (Figure 9). Sertoli Cell Only Syndrome (Del Castillo Syndrome/germ cell aplasia) is characterized by male infertility without sexual abnormality. Only sertoli cells line the seminiferous tubules in testes and germ cells (spermatogonia/ spermatocytes/ spermatids/ spermatozoa) are absent. In general tubular architecture and supporting cells are not affected. Tubular fibrosis or hyalinization is also absent. Sertoli cells play important role in the development of a functional testis. The Sertoli cells secrete anti Mullerian hormone (AMH), inhibin B and lactate to ensure germ cell survival and function (60). In maturation arrest testes fail to produce mature spermatozoa due to interruption of germ cell development and differentiation. Here, germ cells are few or normal in numbers but development & differentiation into spermatozoa is interrupted. Testicular maturation arrest is classified into two distinct subtypes viz., early maturation arrest (mitotic/meiotic arrest; development of germ cells do not advance beyond secondary spermatocyte) and late maturation arrest (post-meiotic/spermieogenesis arrest; differentiation of germ cells do not advance beyond round spermatid) (61). Defects in germ cell proliferation (mitosis) and function with subsequent impairment of meiosis or spermiogenesis cause testicular maturation arrest (51,61,62). Most cases present as early maturation arrest at primary spermatocyte level but can occur earlier at spermatogonial (mitotic arrest) or later at spermatid level (spermiogenic arrest). Hypospermatogenesis is characterized by reduced number of germ cells (all types; spermatogonia, spermatocyte, spermatid and spermatozoa) but usually have normal Leydig cell number/ function. In testicular atrophy basement membrane of seminiferous tubules thicken. The germinal layer is mostly lost (few spermatogonia or primary spermatocytes may be found) and Leydig cells are few (63). However, often one may find differences in subtypes between testes viz., Sertoli cell only syndrome in one testis and tubular fibrosis in other testis or any combinations and these cases are usually labeled as mixed group. In addition many patients may present as complete germinal cell aplasia in some tubules whereas normal spermatogenesis in adjacent tubules (focal germinal cell aplasia) or some tubules with Sertoli cells only or hyaline sclerosis and other tubules with normal spermatogenesis or any other combination. This categorization should be considered as a description of histopathologic phenotypes of spermatogenetic failure and not as manifestations of disease entities. Sometimes, patients may present as hypospermatogenesis or maturation arrest initially and later as sertoli cell only syndrome or testicular fibrosis over a period of few years. Hence diagnosis may change with time. Sertoli cells play important role in development of functional testis. Sertoli cell only syndrome is a common finding of non-obstructive azoospermia. It is a histopathologic phenotype of spermatogenic failure described first by Del Castillo et al. (64). In complete germ cell aplasia, the tubules are reduced in diameter, contain only Sertoli cells and no germ cells are present. The primordial germ cells either do not migrate from the yolk sac into gonadal ridge or do not survive in the seminiferous tubules. Germ cell aplasia also can be focal with a variable percentage of tubules containing germ cells, but even in these tubules, spermatogenesis is often limited (65) and hence, such cases should be categorized as hypospermatogenesis.

Primary testicular failure can result from chromosomal abnormality (Klinefelter syndrome), Yq microdeletion, single gene mutation, etc. Klinefelter syndrome is the most common known cause of primary testicular failure (60,66). It affects approximately 1 in 1000 males (67) and is characterized by one extra X chromosome. Although an extra X chromosome (47,XXY) is the most common form, some men with Klinefelter syndrome have a greater number of X chromosomes or mosaicism (48, XXXY, 46,XY/47,XXY) (68). Infrequently, 46,XX males may present as Klinefelter syndrome (15). The phenotype varies with the number of extra X chromosomes and possibly also with the number of trinucleotide CAG repeats on the androgen receptor gene (a polymorphism). A longer CAG repeat sequence is associated with tall stature, low bone mineral density, gynecomastia and short penile length (69). Men with Klinefelter syndrome generally have small, firm testes resulting from damage to both seminiferous tubules and Leydig cells. Affected men have severely reduced sperm count and are under-virilized (70). Other chromosomal abnormalities associated with primary gonadal failure include the 45,X/46,XY karyotype (mosaicism), causing a syndrome characterized by short stature and other features of Turner syndrome (71). Because the testes may be streak, dysgenetic or normal, the phenotype varies from female to male.

Microdeletions of the long arm of the Y chromosome are now recognized as a relatively common cause of primary testicular failure (severe oligospermia and azoospermia), affecting up to 20% of men with infertility (72). Most microdeletions are mapped to the Yq11 region (named azoospermia factor or AZF). The Yq11 contains three sub-regions such as AZFa, AZFb and AZFc. Deletions of the AZFa or AZFb invariably produce azoospermia whereas deletions in the AZFc region cause infertility of varying severity, ranging from oligospermia to azoospermia. The AZFc deletion is the commonest microdeletion in humans (36). The AZFa region contains DDX3Y and USP9Y genes. These genes have important role in spermatogenesis and deletions of these genes are consistently observed with azoospermia (73,74). The Yq microdeletions have also been observed in men with cryptorchidism, varicocele and obstructions of the vas deferens (75). In our own study on 164 apparent idiopathic primary testicular failure cases we could find out underlying cause in about 21% cases (8.5% sex chromosomal abnormality, 11.6% Yq microdeletion i.e., AZFa,b,c and 0.6% combined sex chromosome abnormality as well as Yq microdeletion).

Normal male sexual differentiation and spermatogenesis require both normal androgen production and normal androgen receptors. The androgen receptor plays an important role in the differentiation of spermatids and their release from the seminiferous epithelium. The number of trinucleotide CAG repeats in exon 1 of the androgen receptor gene is inversely correlated with its transcriptional activity (69). A meta-analysis with 33 published studies revealed that men with spermatogenic disorders had longer CAG repeat lengths (55). Similarly, disorders of estrogen synthesis or action are also associated with spermatogenic defect. Impaired spermatogenesis has been observed in mice and men lacking a functional estrogen receptor alpha (76,77). In mice inactivating mutation in the aromatase enzyme also causes spermatogenic defect (78). Follicle stimulating hormone (FSH) receptor gene mutation too affects spermatogenesis (79). Men with myotonic dystrophy (an autosomal disorder associated with impaired motor function, cataract, premature balding, mild mental retardation and hypogonadism) also exhibit abnormal spermatogenesis (80). Mutations in the SYCP3 gene (involved in regulation of the synapse between homologous chromosomes during meiosis) have been implicated as a potential cause of spermatogenic defect (81). Other genes like DAZL (an autosomal homolog of the DAZ, deleted in azoospermia), PRM1 & PRM2 (protamines involved in chromatin compaction), TNP1 & TNP2 (transition nuclear proteins) and USP26 (deubiquitinating enzyme family) also are implicated with spermatogenic defects (81-83). We are working on various etiological aspects of primary testicular failure, including genotype phenotype co-relation using SNP microarray (84). We found detectable chromosomal cause in 8%, Yq microdeletion (mainly AZFb/c/bc) in 15%, Yq microduplication (mainly AZFc) in 9%, PAR 1 & 2 CNVs in 7% besides few CNVs containing spermatogenesis related genes like SPATA31A2-A5 (9p12). Testicular spermiation defect present as azoospermia despite normal spermatogenesis and in general they do not have any abnormality in chromosome or Yq microdeletion (85). Other well-known genetic mutations associated with male infertility are CATSPER1 (asthenozoospermia), SPATA16 & DPY19L2 (globozoospermia)/ AURKC (macro spermatozoa), etc.

3.2. Pre-testicular failure

The pretesticular (hypogonadotropic hypogonadism or secondary testicular failure) infertility originates from disorder in the pineal, hypothalamus, pituitary or adrenal glands. These extra-gonadal endocrine glands dysfunction have an adverse effect on spermatogenesis through aberrant hormonal action and responsible for infertility in less than 5% of cases. The genetic causes in this group are Kallmann Syndrome (KAL1: Xp22.3; KAL2/FGFR1: 8p11.2-p11.1; KAL3/PROKR2: 20p13; GnRH1: 8p21-p11.2; TAC3: 12q13-21; LEP: 7q31.2; NELF: 9q34.3; CHD7: 8q12.1; DAX1: Xp21.3.-21.2; KiSS1: 1q32.1), CHARGE Syndrome (coloboma, heart defect, atresia of nasal choanae, retardation, genital anomaly & ear anomaly; CHD7 gene: chromo domain helicase DNA-binding protein; 67% of cases due to a CHD7 mutation), Prader Willi Syndrome (15q11-13) (Figure 10), Laurence Moon Syndrome (retinitis pigmentosa, spastic paraplegia, hypogonadism and mental retardation), Bardet–Biedl syndrome (14-15 different genes are involved), gonadotropin-releasing hormone (GnRH) insensitivity (GnRH Receptor mutation: delayed/ reduced/ absent puberty, low or complete lack of libido and infertility; predominant cause of idiopathic hypogonadotropic hypogonadism/IHH when does not present alongside anosmia; Table 3). Patients with hypogonadotropic hypogonadism show delayed puberty due to low sex steroid production along with low levels of serum gonadotropins. Patients with Kallmann syndrome also display an impaired sense of smell due to the developmental failure of the migration of GnRH neurons. Often patient may display cryptorchidism, sparse sexual hair, small testes, micropenis, hypogenitalism, hypogonadism and infertility. Kallmann syndrome is genetically heterogeneous, affects 1:8000 males and less common in females. Kallmann syndrome with ichthyosis in male is categorized as KAL1.

3.3. Post-testicular failure

The post-testicular causes (normo/eu-gonadotropic hypogonadism) of male infertility could be related to sperm motility, morphology, viability, acrosome, or other disorders or obstruction in genital tract. This group constitutes about 5-10% cases of male infertility. The genetic causes in this group are cystic fibrosis (CFTR gene mutations), globozoospermia (DPY19L2 gene homozygous deletion; 12q14.2 or SPATA16 gene deletion/mutation; 3q26.31), necrozoospermia (defect in apotosis or protamine condensation) or sperm chromatin or DNA damage (apoptosis, DNA repair, protamine, etc), etc (Table 4). CFTR mutation is common with non-obstructive azoospermia (10%) and characteristic of congenital bilateral absence of vas deferens/CBAVD (100% association).

4. COPY NUMBER VARIATIONS (CNVs) WITH MALE INFERTILITY

CNVs are submicroscopic chromosome loss or gain that involves several genes. The causal relation between submicroscopic chromosomal rearrangements and impaired sperm production are due to alteration in gene function. CNVs produce effect through loss of gene function or de-masking a recessive mutation on the homologous chromosome or gene disruption or position effect (86). We are working in male infertility using SNP microarray on DNA samples obtained from peripheral blood nucleated cells. The study finds an association between CNVs of PAR 1, 2 & 3 with testicular maturation arrest (84). In another study using X chromosome specific high-resolution comparative genomic hybridization (CGH) array, authors found significantly more X chromosome CNVs in infertile men than controls (87). We have also observed preponderance of CNVs in sex chromosomes, in particular Y chromosome. This indicates that sex chromosomes are extremely important in investigation of azoospermia. Sex chromosome CNVs may cause defective recombination or meiosis and thereby spermatogenic failure (87-90). We have also observed sex chromosome abnormalities, AZF deletions (mostly AZFc), CNVs in pseudo-autosomal regions (PAR 1, 2 and 3), AZFc gain and CNVs containing specific testes/spermatogenesis loci containing genes like SPATA31A2-A5. In male meiosis, the X and Y sex chromosomes do pair in prophase I, thus ensuring that at anaphase I each daughter cell receives one sex chromosome, either the X or the Y (91). The XY pairing is mostly end-to-end and is made possible by a region of homology between the X and Y chromosomes at the tips of their short arms (Xp22.3 and Yp11.32) called PAR 1 (92) and long arms (Xq28 and Yq12) called PAR 2 (93). In some individuals another area in sex chromosomes pairs during meiosis known as PAR 3 (Yp11.2/Xq21.3). Aberrations in chromosome structure or number that disrupt meiotic synapsis are usually associated with gametogenic failure (94) and the impairment of sex chromosome pairing (synapsis) during meiosis is one of the etiological factors underlying maturation arrest (95). Aberrations in sex chromosome number or structure disrupt sex chromosome pairing (synapsis) during meiosis resulting in gametogenic failure (94,95). Errors in meiotic synapsis and recombination are recognized by checkpoints and induce cell cycle arrest and/or apoptosis (96). The sex chromosome pairing in the PAR appears to be critical for meiosis and therefore for spermatogenesis as well. CNVs of the PAR region probably lead to disruption of synapsis by structural aberrations resulting in failure of XY pairing, meiotic arrest and male sterility. PAR regions are rich in genes and escape X inactivation to maintain dosage compensation (97,98). PAR genes (PAR 1: AKAP17A, ASMT, ASMTL, CD99, CRLF2, CSF2RA, DHRSX, GTPBP6, IL3RA, P2RY8, PLCXD1, PPP2R3B, SHOX, SLC25A6, XG, ZBED1; PAR 2: IL9R, SPRY3, VAMP7, AVPR2, CXYorf1 and PAR 3: PCDH11Y, TGIF2LY) are dosage sensitive and hence CNVs (deletions or duplications) of PARs result in under or over expression of genes and could lead to pathological phenotype. PAR1 harbors PPP2R3B (PR48) gene, which has a potential role in spermatogenesis. Functional evidence supports its involvement both in mitosis and meiosis (cell cycle negative regulator). PPP2R3B (PR48) encodes for a subunit of the protein phosphatase 2 (PP2) protein complexes (99). PPP2R3B maintains pool of dephosphorylated CDC6 replication licensing factor (99). CDC6 phosphorylation and dephosphorylation is necessary for the mitotic G1 to S phase transition (100) and the overexpression of PPP2R3B disturbs cell cycle progression, causing a mitotic arrest at G1 phase. Expression analysis of testis biopsies supports involvement of PPP2R3B in mitosis (101). PAR 2 contains various functional genes like H2AFB1 (2-copies), H2AFB2 (2), H2AFB3 (2), F8A1 (2), F8A2 (2), F8A3 (2), TMLHE (2), SPRY3 (1), IL9R (2) and VAMP7. The genes in PAR 2 seem not to be directly linked to cell cycle, meiosis and/or spermatogenesis, except H2AFB family genes (histone family, member B1, B2 and B3). Unlike canonical histones that function primarily in genome packaging and gene regulation, H2AFB, a variant histone has role in DNA repair, meiotic recombination, chromosome segregation, transcription, sex chromosome condensation and sperm chromatin packaging (102). The imbalances of these genes caused by PAR 2 CNVs may have an impact on spermatogenesis leading to spermatogenic arrest. Impairment of spermatogenesis also can be explained through a structural defect affecting recombination event in gene independent manner. Hence, it is important to study CNVs of pseudo-autosomal regions besides sex chromosome aneuploidy and mosaicism.

The role of gain in AZFc region as underlying etiopathology in nonobstructive azoospermia is controversial. Lin et al. (103) reported that men with partial AZFc duplications that result in increased AZFc gene copies were at increased risk for spermatogenic impairment. Similarly, men with only AZFc duplications and without any AZFc deletion, resulting excess copies/ over dosage of DAZ genes, are in a disadvantageous position for normal spermatogenesis (104). Other CNVs containing genes like MYRIP, LRRC4C, RNA LOC100507205, EDDM3A, EDDM3B, HLA-DRB1, HLA-DQA1, POTE B, GOLGA8C, DNMT3L, ALF, NPHP1, NRG1, RID2, ADAMTS20, TWF1, COX10, MAK, DNEL1, SUN5 (20q11.21), SPATA6 (1p33), SPATA4 (15q26.2), SPATA12 (3p14.3), SPATA17 (1q41), SPATA8 (15q26.2), SPATA, TEX101 (19q13.31), BEX2/1 (Xq22.1), MAATS1 (3q13.33), RNF141 (11p15.4), PBK (8p21.2), C17orf75 (17q11.2), SPATA42 (1p13.3), UBE2B (5q31.1), KIT (4q12), SPATA31A, etc are reported with spermatogenic arrest (105-108). Many more reports observed an increased frequency of CNVs in infertile men compared to controls (88,109,110) including sex chromosomes & deletion of Xp11.23 (89) (Table 5).

5. EPIGENETIC MODIFICATION IN MALE GAMETOGENESIS AND MALE INFERTILITY

Epigenetic is alteration in the gene function without affecting basic DNA sequence i.e., change in phenotype without changing genotype. These alterations are mainly addition of different molecules to the DNA, which then changes the regulation of gene function. The main epigenetic mechanisms of gene regulation are DNA methylation, histone modifications and non-coding RNAs. In DNA methylation DNA methyl transferase enzyme adds methyl group from s-adenosyl methionine as methyl donor to 5’ carbon of cytosine resulting in CpG dinucleotide. DNA methylation is involved in genomic imprinting, X chromosome inactivation and gene silencing. Histone modification requires various enzymes like histone methyltransferase, histone acetyl transferase, ubiquitin enzymes, etc and is involved in DNA methylation, acetylation, phosphorylation, ubiquitinylation, etc and regulate DNA replication, repair, recombination and gene expression. Non-coding RNA do not code for protein but regulate gene expression and plays role in imprinting, X inactivation, gene silencing, etc.

Most important contribution of sperm to the zygote, beside nucleus, is functional centrosome. Functional centrosome is important for orderly chromosome segregation. Immature sperm does not have a functional centrosome, thus if used for fertilization during assisted reproduction, will lead to error in chromosome segregation and aneuploid embryo (111). Abnormal centrosomes may also cause cleavage arrest (112). The imprinted regions of DNA are reset in every reproductive cycle (113). Chromatin packaging is another essential step in sperm development and during the process histones are replaced by protamines. Abnormalities in protamines (protamine 1/P1 and protamine 2/P2) affect spermatogenesis (114). P2 is associated with sperm DNA damage and abnormal packaging of chromatin (115). P1 or P2 gene mutation or alteration in P1 & P2 protein ratio may also cause male infertility (116).

There are four windows of susceptibility of epigenetic effect (117) in male reproduction. The first window is during development of gonad, when primordial germ cells undergo genome wide epigenetic erasure during migration to the genital ridge. The second window is during prepuberty. The third window is during spermatogenesis, specifically during transition from spermatogonium to spermatocytes & spermiogenesis stage. Finally, the fourth window is represented by the peri-fertilization period.

Alterations in sperm count, morphology, DNA fragmentation and aneuploidy could also be related to epigenetic mechanisms occurring at different stages of spermatogenesis. The last phase of spermatogenesis is spermiogenesis, which is characterized by a morphological transformation of the round spermatid. This leads to the production of mature sperm, characterized by the tail/ flagellum and the acrosome, prerequisites for sperm motility and fertilization. During spermiogenesis sperm DNA also undergoes condensation due to the replacement of over 90% of the histones with protamines (118). This modification improves sperm motility, protects from oxidative stress as well as toxic agents and blocks transcriptional activity of the sperm DNA (119). The effect of epigenetic modification of sperm can affect reproduction and also transmits to offspring. Several environmental and lifestyle factors such as stress, physical activity, alcohol intake, smoke, shift work, etc may affect male fertility (120) and in many cases the effect is mediated through epigenetic modifications (121).

Epigenetic alterations could account for at least a portion of cases of male infertility in which no genetic abnormalities are detected. Alterations of genomic imprinting cause several diseases mainly involving fetal growth (growth abnormalities: underweight or overweight), hormonal balance (e.g., Albright hereditary osteodystrophy, pseudohypoparathyroidism 1A, transient neonatal diabetes mellitus) or behavior (e.g., Prader Willi syndrome, Angelman syndrome) (122). An increased incidence of Angelman syndrome or Beckwith Wiedemann syndrome is reported in offspring from ICSI/ART procedures (123,124). Epigenetic reprogramming through mitotic or meiotic crossover during spermatogenesis has important effect on the normal fertilization as well as embryonic development and its dysregulation leads to infertility, abortion, malformation, growth disturbance (over or underweight), premature aging, cancer, etc. ART procedures, in particular intracytoplasmic sperm injection, cloning (with somatic nucleus), induced pluripotent stem cell derived offspring, etc produce epigenetic abnormalities. Environmental agents can also influence human heredity (125), mainly through epigenetic mechanism.

6. EVALUATION

The evaluation of a male with infertility is performed to determine the etiology, prognosis, treatment options and counseling. The first step of evaluation is semen analysis. Azoospermia is diagnosed when no spermatozoa can be detected on high power microscopic examination of centrifuged (for 15 minutes at a centrifugation speed of 3000g or greater) seminal deposits on at least two occasions at an interval of 3 months (preferably). The initial important evaluation to determine cause & type should include fertility history, mumps, cryptorchidism, genital trauma or history of inguinal/scrotal surgery, genital infection such as filariasis/tuberculosis, gonadotoxin exposure such as radiation/chemotherapy or heat exposure and current medications. Family history of cystic fibrosis is also considered. Physical examination should include secondary sex character, body mass index, testis (size & consistency), epididymis (nodule/cyst/varicocele), vasa deferentia (present/absent), etc. The initial hormonal evaluation should include measurement of serum testosterone, prolactin and FSH levels followed by inhibin B &/or AMH estimation. One ultrasound-doppler study should be advised to exclude varicocele. Finally testicular fine needle aspiration cytology (FNAC) or testis biopsy is required to confirm diagnosis and categorize. Figure 11 reproduces algorithms that may assist in the assessment and direct type of investigations for infertile male. Table 6 outlines important genetic tests that are worth investigating in order to find out underlying etiology of male infertility that may assist in counseling the patient and probably management of infertile male as well.

FSH is the classical endocrine parameter to discriminate testicular impairment of spermatogenesis from obstructive as well as pretesticular disorders. FSH level is also a valuable predictive marker of the histological picture of the testis (126) but due to wide overlap between values in normal control and reduced spermatogenesis limits its diagnostic accuracy (127). Inhibin B is another important spermatogenesis marker in men. Inhibin B is secreted from the Sertoli cells of the testes. Inhibin B selectively suppresses the secretion of FSH, has local paracrine actions on the gonads and appears to be involved in the regulation of gametogenesis. In adult male, serum level of inhibin B is stable throughout life. Inhibin B expression and secretion in men is positively correlated with Sertoli cell function & number, sperm number and spermatogenic status and negatively correlated with FSH. It is a good marker of spermatogenesis and may offer an improved diagnosis of testicular dysfunction (126,128). Anti Mullerian Hormone (AMH) is produced from the Sertoli cells of testes in male. AMH blood concentration decreases dramatically during puberty and persists at low value in adult. Undetectable or very low AMH reflects a primary alteration in Sertoli cell function. However, its value in men with maturation arrest or hypospermatogenesis or oligozoospermia is controversial (129).

In our experience inhibin B seems to be a good predictor/marker of primary testicular failure. In Sertoli cell only syndrome (SCOS) FSH is also a good marker along with inhibin B (126). The classic predictors of spermatogenesis are testicular size, semen analysis, FSH level and testicular histology. However, in our experience we have found frequently contradicting findings viz., small testicular size with better seminal parameters or SCOS with occasional sperm in semen. We have observed lower predictive value of FSH with maturation arrest (MA) as well as hypospermatogenesis (HS). The FSH value is often normal in these subgroups. Inhibin B seems a better predictor in these situations. This is also supported by observation of more accurate prediction of the presence of testicular spermatozoa in nonobstructive azoospermia with the level of serum inhibin B. Estrogen is involved in the negative feedback effects of testosterone and controls pituitary gonadotropin secretion. The role of estrogen in male is still a matter of debate even though there is a growing body of evidence suggesting that estrogen plays a role via their specific receptor (ERα and β) that are present throughout the genital tract besides its effect on gonadotropin secretion. In our experience estrogen plays a role in some early maturation arrest cases as evidenced by elevated level of estradiol.

Various tests are now available to explore the genetic cause of male infertility. Genetic tools used for the evaluation of male infertility are chromosomal analysis (conventional cytogenetics & FISH), Yq microdeletion, CGH/SNP microarray (DNA microarray), epigenetic/methylation microarray (DNA methylation microarray), long noncoding RNA (lncRNAs) microarray, mutation analysis by PCR/DNA sequencing and next generation sequencing (NGS) for gene panels/whole exome or whole genome sequencing. Conventional cytogenetics is usually carried out using lymphocyte cell culture for 72 hours. A mitotic inhibitor (colchicine) is added after 70 hours of culture, cells are incubated again for 2 hours to arrest cells in metaphase Thereafter the cells are treated with hypotonic solution (50 mMol KCL) followed by fixation in Carnoy’s solution (methanol: acetic acid). Fixed cells are spread over glass slide, banded with Geimsa Tripsin Geimsa (GTG) staining and are evaluated under light microscope for abnormalities. FISH is carried out most frequently using commercially available FISH probes on metaphase spread chromosomes or interphase cell nuclei. The probe and nuclear DNA are denatured together on to a glass slide, hybridized overnight at 37°C, washed with NP40, dehydrated in ethanol series, mounted in antifade containing DAPI (4,6 diaminidino-2- phenylindol) and are screened under fluorescent microscope using plan-apochromatic objective and single band pass filter for DAPI, FITC, TRITC, etc flurochromes (depending upon flurochrome used for labeling FISH probes). Presence of two signals in 100 per cent metaphases and/ or 90 per cent interphase cells are considered as normal. Sequence tagged sites (STS) PCR is performed to confirm AZF deletion using commercially available 20 primer pairs for known STS (Promega, USA) or 6 primer pairs (2 each for AZFa, AZFb & AZFc regions). Absence of amplification proves deletion. PCR technique is used to amplify a single copy or a few copies of a piece of DNA (usually few hundred base pair size) to several orders of magnitude for easy visualization. It is based on the ability of DNA polymerase enzyme to synthesize new strand of DNA complementary to the template strand. The PCR reaction generates copies of the target sequence exponentially. SNP microarray is carried out using commercially available DNA/SNP arrays (Illumina, Affimetrix, Agilent, etc) and interpretation is based on optical intensity. Here only the test DNA is labeled with flurochrome and its incorporation is proportionate to optical intensity (more the incorporation greater will be the optical intensity). In contrast, array comparative genomic hybridization (CGH) utilizes relative incorporation of probes (labeled test DNA vs. normal control DNA) on known DNA spots (instead of normal metaphase spread, as with CGH). This utilizes DNA hybridization principle i.e., more the initial DNA more will be the incorporation. Hybridization image is captured on specific scanner and primary data is analyzed using system specific softwares. Resolution is preferably set as 0.1 mb for CNVs whereas 5 mb is set for loss of heterozygosity (LOH). Secondary analysis of CNV may be carried out by web database resources viz., DECIPHER, OMIM, Gene, GeneCards, etc and compared with normal control databases &/or control sample data. Epigenomic microarray (Illumina 450K infinium methylation bead array) may be used to study epigenomic abnormalities. DNA methylation is measured using bisulfite-converted genomic DNA. After bisulfite treatment, unmethylated cytosine bases are deaminated to uracil, while methylated cytosine bases remain unchanged. The assay interrogates these chemically differentiated loci using one or two site specific probes (bead types) per CpG locus. The level of methylation for the interrogated locus is determined by calculating the ratio of the fluorescent signals from the methylated vs. unmethylated sites. It covers 96% of CpG islands, with multiple sites within islands and island shores, as well as island shelves. To assess the overall functionality of the individual CpG assays on Human Methylation 450, three human genomic DNA methylation reference standards viz., unmethylated (U, 0%), hemi-methylated (H, 50%) and methylated (M, 100%) controls are used. Software are used to analyse data and view results as heat maps, scatter plots, and line plots besides information on chromosomal coordinates, percent GC, location in a CpG island, and methylation β values. Long non-coding RNAs (lncRNAs) are conserved, longer than 200 nucleotides non-coding RNA molecules. LncRNAs are important regulators for diverse functions and are involved in cellular functions, including epigenetic silencing, transcriptional regulation, RNA processing and RNA modification. LncRNAs are associated with human diseases such as cancers, Alzheimer’s disease, heart diseases, etc. LncRNAs microarray is used to profile lncRNAs along with the entire set of protein-coding mRNAs. The lncRNA data analyses and annotation softwares unravel the complex lncRNA biology and regulatory relationships with the protein coding genes. Next generation sequencing (NGS) can be used for chromosomal analysis (including identification of balanced translocation using long read methods) as well as mutations in genes. It uses massively parallel whole genome sequencing or targeted sequencing (selected chromosomal regions of interest or gene panels) or SNP based targeted sequencing. Massively parallel sequencing usually covers whole genome and gives information on all chromosomes & sub-chromosomal regions or genome. Targeted sequencing covers few chromosomal loci or panel of genes and hence less informative. SNP sequencing is highly sensitive & specific for chromosomal analysis; can also detect triploidy, uni-parental disomy, maternal contamination besides microdeletion syndromes and specific gene mutations.

Based on prevalence data routine karyotyping of infertile men with unexplained spermatogenic failure is widely recommended for finding etiology as well as before going for ART. Sperm FISH is also commonly used to determine the proportion of aneuploidy present in sperms of infertile men with oligospermia, teratospermia, testicular/ epididymal sperms, etc. Testicular sperm from men with nonobstructive azoospermia display higher rate of aneuploidy in spermatozoa than ejaculated sperms. Sperm aneuploidy test (FISH) is indicated in oligospermia, nonobstructive azoospermia (testicular sperm), teratozoospermia, necrozoospermia, Klinefelter’s syndrome (mosaic and nonmosaic), translocations, exposures to gonadotoxins, chemotherapy, pesticides exposure, repeated ART failures, etc. Sperm chromosomal study (FISH) aids counseling regarding PGD or alternative reproductive options. Y chromosome microdeletion/AZF deletion study is also indicated in non-obstructive azoospermia and oligospermia. Testing of AZF deletions has a prognostic impact for sperm extraction, since no sperm can be retrieved in AZFa deletion, while there is a fair chance of retrieving sperm in AZFc deletion.

Sperm chromatin compaction is increased twenty-fold compared with somatic cells following the replacement of 90–95% of histones in the sperm genome by the highly negatively charged nucleoproteins, protamine. Integration of protamine 1 and protamine 2 into the sperm genome during the elongation phase of spermatogenesis (in particular spermiogenesis) normally occurs in a strictly controlled 1:1 fashion. Significant deviations in the ratio have been associated with alteration in motility, morphology, and fertilization capacity as well as increased DNA fragmentation (130). Sperm DNA integrity is associated with semen characteristics and has an influence on fertilization, embryo quality and pregnancy outcome in conventional IVF. Sperm DNA integrity is disturbed in male genital infection, oxidative stress, exposure to pollutants, etc. At present, the results of sperm DNA integrity testing alone do not predict pregnancy rates achieved through natural conception (130).

Monogenic disorders associated with male infertility are Kallmann syndrome, Laurence Moon Biedl syndrome, Prader Willi syndrome, Noonan syndrome, androgen receptor mutations or trinucleotide expansion, FSH/LH (luteinizing hormone) receptor mutation, mitochondrial gene defects, etc and tests for detecting these mutations may be offered in specific cases. CNVs have not yet been defined as a cause of male infertility, but that seems inevitable. Link between epigenetics and male infertility involves protamine packaging of the sperm genome. However, it is clear that homozygous mutations in key epigenetic regulators affect male fertility. For couples failing multiple attempts at IVF/ICSI, additional testing with sperm FISH may be advised as elevated sperm aneuploidy rates have been observer among couples with repeated ICSI failures (131).

7. MANAGEMENT

Generally, patients are categorized into three groups. First group includes patients who can be diagnosed and treated by existing technology, for example, patients with hypogonadotropic hypogonadism. Unfortunately, this group is the smallest. Second group includes patients who can be diagnosed, but cannot be treated by existing technology, such as patients with primary testicular failure having AZF microdeletions or chromosomal aneuploidy (Klinefelter syndrome) as underlying cause of infertility. Third group includes patients who can neither be diagnosed nor treated. . Majority of male infertile patients fall in this group. It is probable that knowledge of the underlying genetics may improve treatment options. Finally, the ultimate goal will be direct correction of underlying genetic defects (132).

Pre-testicular failure or hypogonadotropic hypogonadism (example Kallmann’s syndrome) can be treated by pulsatile infusion of GnRH with a portable minipump or alternatively by HCG and FSH (preferably by recombinant FSH/rFSH & recombinant HCG/rHCG). In view of the length of the spermatogenetic process, the treatment should be continued until spermatozoa appear in the ejaculate, which may take even one year (133).

Genetic abnormalities associated with the disorder are usually inherited and transmitted to offspring when patients opt for assisted reproduction; hence genetic counseling should be provided to patient once genetic etiology is detected. It is important to investigate idiopathic cases at genomic and epigenomic levels to find out the underlying causes. In azoospermic men with focal spermatogenesis or hypospermatogenesis or late maturation arrest, pregnancies can be achieved with testicular sperm extracted and injected into mature oocytes by ICSI. Similarly, in vitro spermatogenesis of germ cells obtained by testicular biopsy in these cases may result in pregnancy & live birth in near future.

In general, primary testicular failure of genetic/idiopathic origin is associated with very poor fertility even with assisted reproductive technologies. Currently there is no therapy for primary testicular failure with complete germ cell aplasia. Management of primary testicular failure involves avoiding risk factors as preventive measure &/or early diagnosis along-with early appropriate preventive management. Early management of varicocele &/or cryptorchidism may result in restoration of fertility. The risks arising from chemotherapy, radiation or surgery can be minimized by judicious planning and adopting preventive measures (care during surgery, prior cryopreservation of gamete/gonadal biopsy and following protective measures during radiotherapy). Infertility is an undesirable side effect of oncotherapy. Currently semen sample banking is suggested to cancer patients prior to cancer treatment. However sperm banking is not possible for pre-pubertal boys. In such cases, testicular tissue banking is advocated prior to oncotherapy to achieve biological parenthood later in life, if the patient survives (134,135). The testicular biopsies are preserved either as intact small pieces or as cell suspension comprising germ cells. In future, the cell suspension can be transplanted into the seminiferous tubules or testis tissue pieces could be grafted at heterotopic sites to obtain sperm for assisted reproduction or spermatogonial stem cells can be matured in vitro to produce sperm. Germ cells transplantation leading to birth of mouse pups has been reported (136,137). An alternative approach to germ cell transplantation is to xenograft testicular tissue biopsy (with intact somatic environment) in immuno-deficient mice (138). This approach has resulted in complete spermatogenesis and sperm production from newborn mice, pigs and goats testicular grafts transplanted in nude mice (139). At present, it is suggested that we should bank prepubertal gonadal tissue of cancer patients prior to treatment that may help them restore fertility later using assisted reproduction although use of cryo-preserved testicular tissue to restore spermatogenesis is not yet established in human. Embryonic stem cells or induced pluripotent stem cells also can be differentiated in vitro to produce sperm. Various publications discussed in depth on artificial gametes and suggested that the use of artificial gametes to treat infertility will take some more time to come into practice (140-142).

Recent studies have shown that a novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) exists in normal and azoospermic human testes. Studies on mice show that VSELs survive cancer therapy because of their quiescent nature and can be isolated from chemo-ablated testis and undergo spermatogenesis when healthy niche (Sertoli or mesenchymal) cells are directly transplanted into the chemo-ablated testis. Several groups have reported beneficial effects and live births on transplanting mesenchymal cells in chemo-ablated rodent/mouse testes (143-146). VSELs may also be isolated from bone marrow and can be differentiated into germ cells (147). If this is true then there may be no need to even discuss fertility issues with cancer patients. There may not be a need to even wait till the individual wishes to plan his family. An early transplantation of mesenchymal cells may restore gonadal function and may help in achieving better secondary sexual development and avoid hormone replacement therapy, which is currently practiced to manage development and growth issues of cancer survivors. It is also worth experimenting using VSELs and mesenchymal cells (bone marrow derived) in primary testicular failure of genetic origin to restore fertility.

Predictive genomic medicine will help in identifying individual who are at risk of having non-obstructive azoospermia in future and will give them time to plan for gonad cryopreservation/ gamete cryobanking or use of stem cells viz., VSELs in order to counter future problems. Most cases of primary testicular failure of genetic etiology are presented as normal spermatogenesis in younger age group however spermatogenesis decreases rapidly over a period of few years after puberty indicating accelerated programmed death of germ cells. In future predictive medicine approaches will identify these cases and appropriate preventive measures may be instituted before complete testicular failure occurs.

8. IMPORTANCE OF EXPLORING GENETIC BASIS OF MALE INFERTILITY

The advent of ART such as ICSI allows men with suboptimal sperm quality (often associated with genetic defects) to produce a child of their own. This ART procedure may lead to the transmission of genetic defect and possibly additional epigenetic modifications from in vitro manipulation to the embryo, which may affect future generations. At present, there is no definite evidence of significant increase in imprinting disorders (148) or aneuploidy of sex chromosomes (from 0.2% to 0.6%) and autosomes (from 0.07% to 0.4%) associated with ART procedures (149). However, it is our responsibility to find out the underlying genetic etiology of male infertility in order to prevent transmission to offspring for example, transferring chromosomally normal embryo (through preimplantation genetic diagnosis) in Klinefelter syndrome. In general, Klinefelter syndrome male is believed to be sterile, but it has been estimated that 25% of non-mosaic and over 70% mosaic Klinefelter syndrome males have sperm in their ejaculate (2,13) in younger age. These patients have chance to father a normal pregnancy using ICSI (as number of sperms are few) and preimplantation genetic diagnosis (which will help in selecting euploid embryo from large number of aneuploidy embryos being formed due to high frequency of aneuploid sperms) (150,151). Preimplantation genetic diagnosis should be performed before embryo transfer to ensure that the offspring is not aneuploid (148). Similarly, male infertility due to Yq microdeletions (AZFa,b,c) are common and can be managed by ART, in particular ICSI procedure. Here, it is essential to know that Yq microdeletions will pass on to all male offspring hence it is essential to discuss these issues with couple before going for ART (152). Alternatively, female zygote (confirmed by preimplantation genetic diagnosis) may be used to achieve pregnancy leading to birth of healthy female child.

9. HOW TO PREDICT AND PREVENT MALE INFERTILITY USING GENOMICS?

Traditionally it is believed that genetic disorders are untreatable. Now this concept is changing. The major contribution of genetics is to predict and prevent a disorder thus decreasing its burden right from the planning of reproduction. Genetic factors are greatly responsible for infertility, pregnancy losses, malformation and cancer. The ideal time to apply genetics should be from the time of gametogenesis to peri-conception period so that prediction and/or prevention (primary and/or secondary) is possible. Advances in molecular technologies (NGS and microarray) as well as reproductive technologies (preimplantation genetic diagnosis/PGD, assisted reproductive technology/ART, etc) have increased this drive and expectations. Rapid dissemination of information in media has affected daily reproductive care so much that an understanding of genetics is essential for all reproductive specialists, in particular how to predict and prevent a disorder. This would be of much use to young cancer patients wanting to father a child in future as their survival rate is increasing. Genetics is becoming more important following the development of in vitro fertilization (IVF) and intra cytoplasmic sperm injection (ICSI) as these procedures lead to more genetic as well as epigenetic abnormality in offspring. The use of ICSI has raised major concerns about safety of the offspring, since it bypasses the physiological protective mechanisms related to normal fertilization. Natural selection prevents the transmission of mutations causing infertility. This protective mechanism is bypassed in ART. The risk for genetic causes of infertility thus will increase in future generations conceived through ART (153), if no preventive measures adopted.

Advances in reproductive technology like cellular reprogramming or cellular differentiation or dedifferentiation have created another dimension in reproduction. Now, in the laboratory stem cell can be manipulated to become specialized cells and can be used to treat disease. Embryonic stem cells can be differentiated into gamete (sperm or oocyte) to treat infertility. Recent progress in germline stem cell isolation and culture may provide a platform for in vitro gamete development and may open a new era of gametogenesis in a dish and personalized infertility treatment in coming years (144,154). For therapy with stem cells, the issue of immuno-compatibility arises. The breakthroughs in somatic cell nuclear transfer have raised the possibility of generating unlimited sources of undifferentiated cells, with potential applications without immune rejection. However, all these procedures will lead to transmission of underlying genetic cause as well as likely additional epigenetic problem into offspring which will require specific counseling and preventive strategy.

The genomic screening technology has enabled the detection of genetic etiologies (chromosomal abnormalities, Yq microdeletion, CNV, gene mutation, etc) implicated in male infertility. This creates opportunities for the development of more precise and early detection, even at preimplantation or prenatal or neonatal or childhood stage. The growing possibility of infertility prediction may make prevention and early precision treatment a reality. It is also likely that epigenetic profiling of spermatozoa from infertile men may be useful in the near future, including assessing the potential of the spermatozoa to contribute to normal embryogenesis and in assessing risks associated with environmental exposures (155).

Once genomic technologies (DNA microarray and/or NGS) are in use for screening genetic etiologies (testicular, pre-testicular, post-testicular or combinations gene panels; Table 6) of male infertility as part of predictive medicine practice, high-risk groups may be identified before development of disease and appropriate measures may be started much before the pathology appears. Cases like Klinefelter syndrome, Yq microdeletion, hypogonadotropic hypogonadism, etc where pathology manifests after puberty may benefit in future through predictive genomic medicine practice (prediction before disease manifestation followed by preventive measures like gonad/gamete cryopreservation & use later when required through in vitro or in vivo gametogenesis or treating with deficient hormones in hypogonadotropic hypogonadism). It is possible to construct a logical screening program of genes panel for mutation, chromosomes abnormalities, CNVs and Yq microdeletions causing infertility. However, there are many unknown etiologies are involved in the control of spermatogenesis. Identification of these unknown factors may open up newer avenues for therapeutic and diagnostic approaches. With the better understanding of the underlying cause of male infertility as well as continued advances in genomics and epigenomics, it is likely that the hope of personalized medicine in male infertility will be realized in coming years and personalized genomic approaches to predict, prevent and manage male infertility will improve our ability to care infertile couples.

10. ACKNOWLEDGMENTS

The authors declare that there is no conflict of interest. Authors acknowledge the patients for their invaluable cooperation. Authors also acknowledge various departments of the All Indian Institute of Medical Sciences (AIIMS) for referring patients. We are grateful to Professor VK Iyer (pathology department, AIIMS) for providing microphotographs of FNAC testes from primary testicular failure cases.

11. REFERENCES

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Key Words: Male Infertility, Genetic causes, Genomic causes, Prediction and Prevention strategies, Review

Send correspondence to: Ashutosh Halder, Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi 110029, India, Tel: 91-11-26594211, Fax: 91-11-26588641, E-mail: ashutoshhalder@gmail.com