The long and short arms of the Y-chromosome contain many genes that regulate spermatogenesis and testis development, respectively. Microdeletions on the long arm of the Y-chromosome (Yq) are well correlated with male infertility. Yq microdeletions are detected in approximately 13 % of men with NOA and in 5 % of men with severe oligozoospermia (sperm counts lower than 5 million/mL) (Reijo et al. 1995; McLachlan et al. 1998). A microdeletion is defined as a chromosomal deletion that spans several genes but that is small in size and cannot be detected using conventional cytogenetic methods (e.g., karyotyping). The region at Yq11 is referred to as the “azoospermia factor” (AZF) region. The AZF region is further subdivided into three subregions that are termed AZFa, AZFb, and AZFc. The most common aberrations in the AZF region are multiple gene deletions in the AZFb and AZFc subregions (Ferlin et al. 2007b), which can produce a wide range of infertility phenotypes.

Three regions in the long arm of the Y-chromosome, known as AZFa, AZFb, and AZFc, are involved in the most frequent patterns of Y-chromosome microdeletions. These regions contain a high density of genes that are thought to be responsible for impaired spermatogenesis. In 2003, the Y-chromosome sequence was mapped, and microdeletions are now classified according to the palindromic structure of the euchromatin that is composed of a series of repeat units called amplicons. Although it has been shown that the AZFb and AZFc are overlapping regions, the classical AZF regions are still used to describe the deletions in clinical practice (Sadeghi-Nejad and Farrokhi 2007). Y-chromosome microdeletions are among the major causes of male infertility.

Both the European Academy of Andrology (EAA) and the European Molecular Genetics Quality Network (EMQN) have recommended the use of sY84 and sY86 markers for the detection of azoospermia factor a (AZFa) microdeletion during DNA testing for male infertility (Wu et al. 2011). Detection of various subtypes of these deletions has a prognostic value in predicting the potential success of testicular sperm retrieval for assisted reproduction. Men with azoospermia and AZFc deletions may have retrievable sperm in their testes. However, with ICSI, there is a risk of transmission of these microdeletions to the male offsprings (Mau Kai et al. 2008). There is a high-frequency genetic abnormality, such as Y-chromosome microdeletions in patients of NOA, and a risk of passing the genetic defects to their offspring. Consequently, there is need for genetic testing and counseling of NOA patients prior to ART. The genetic testing may also be useful in prognosis and choice of ART technique. A high prevalence of Y-chromosome microdeletions have been observed in Middle Eastern (28.41 %) (Alhalabi et al. 2013), Ukrainian (35 %) (Pylyp et al. 2013), Brazilian (18.8 %) (Mafra et al. 2011), and Iranian patients (66.67 % of AZFb) (Mirfakhraie et al. 2011), but the incidence seems to be low in Slovak azoospermic patients (Behulova et al. 2011). Genetic anomalies in patients with severe oligozoospermia and azoospermia have also been detected in eastern Turkey. A prospective study detected Y-chromosome microdeletions, especially of the AZFc locus to the extent of 64 % (Ceylan et al. 2010). The most frequent deletions were in the AZFc region (50 %) in Thai men with azoospermia and comparable with infertile men from other Asian and Western countries (Vutyavanich et al. 2007).

About 10 % of cases of male infertility are due to the presence of microdeletions within the long arm of the Y-chromosome (Yq). Despite the large literature covering this critical issue, very little is known about the pathogenic mechanism leading to spermatogenesis disruption in patients carrying these microdeletions. Testicular gene expression profiling of patients carrying an AZFc microdeletion has been carried out by employing a microarray assay techniques. Results indicated a downregulation of several genes related to spermatogenesis that are mainly involved in testicular mRNA storage. If that several forms of infertility can be triggered by a common pathogenic mechanism, that is likely related to alterations in testicular mRNA storage due to lack of testicular DAZ gene expression (Gatta et al. 2010).

Maturation arrest (MA) refers to failure of germ cell development leading to clinical NOA. Although the azoospermic factor (AZF) region of the human Y-chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. Stahl et al. (2012) have attempted to identify single genes on the Y-chromosome that may be implicated in the pathogenesis of NOA associated with MA in the American population. Based on the genotype-phenotype analysis of 132 men with Y-chromosome microdeletions, they identified CDY2 and HSFY as the genes for which differences in expression were observed between the MA and OA. Men with OA had 12-fold and 16-fold higher relative expression of CDY2 and HSFY transcripts, respectively, compared to MA. CDY2 and HSFY were also underexpressed in patients with Sertoli-cell-only syndrome. These observations suggest that CDY2 and HSFY are important for sperm maturation, and their impaired expression could be implicated in the pathogenesis of MA.

Genetic mechanisms implicated as a cause of male infertility are poorly understood. Meiosis is unique to germ cells and essential for reproduction. The synaptonemal complex is a critical component for chromosome pairing, segregation, and recombination. Hormad1 is essential for mammalian gametogenesis. Mutational analysis of all HORMAD1 coding regions in Japanese men revealed meiotic arrest in the early pachytene stage, and synaptonemal complexes could not be visualized. By the sequence analysis, three polymorphism sites, SNP1 (c. 163A > G), SNP2 (c. 501 T > G), and SNP3 (c. 918C > T), have been found in exons 3, 8, and 10. SNP1 and SNP2 were associated with human azoospermia caused by complete early maturation arrest (P < 0.05) (Miyamoto et al. 2012a). In similar studies, SEPTIN12 and UBR2 gene have also been found to be associated with increased susceptibility to azoospermia caused by meiotic arrest (Miyamoto et al. 2011, 2012b). Mutations in PRDM9 (MEISETZ) gene have also been implicated in Japanese NOA patients (Irie et al. 2009; Miyamoto et al. 2008).

Specimens from testicular biopsies of men with NOA have been used to investigate the expression of spermatogenesis-related genes MND1, SPATA22, GAPDHS, and ACR. Analysis of the expression of spermatogenic genes in human testes with abnormal spermatogenesis showed different expression patterns in patients from the three groups: hypospermatogenesis (HS), maturation arrest (MA), and Sertoli-cell-only syndrome (SCO) groups. Fertilization rates were similar at 70 %, but pregnancy rates for ACR and GAPDHS genes were low at 6–8 % (Dorosh et al. 2013).

A genome-wide association study in Chinese population has revealed that variants within the HLA region are associated with risk for NOA (Zhao et al. 2012). They have detected variants at human leukocyte antigen (HLA) regions, HLA-DRA, rs3129878, and rs498422 to be independently associated with NOA.

Recently, a separate Chinese genome-wide association study (GWAS) (Hu et al. 2012) identified four autosomal single-nucleotide polymorphism (SNP) loci as being significantly associated with risk factors for NOA: rs12097821, rs2477686, rs10842262, and rs6080550. Although not significant, three of four SNPs (rs12097821, rs2477686, and rs10842262) have also showed associations in Japanese men. However, further larger case–control studies are required to establish whether the SNPs are genetic risk factors for NOA in these populations (Sato et al. 2013). C677T in the methylenetetrahydrofolate reductase (MTHFR) gene is also suggested as a genetic risk factor in Chinese men (A et al. 2007).

A genome-wide gene expression study by Okada et al. (2008) demonstrated that SNPs (rs6836703) of the ADP-ribosyltransferase 3 gene (ART3) were associated with NOA with highest significance. These findings clarify a molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA. MicroRNAs (miRNAs) are a class of small noncoding RNA molecules. The expression of miRNAs is altered in testicular tissues of patients with NOA, suggesting a role of miRNAs in regulating spermatogenesis (Lian et al. 2009).

Nonetheless, at least 40 % of cases are currently categorized as idiopathic and may be linked to unknown genetic abnormalities. It is recommended that various genetic screening tests are performed in azoospermic men, given that their results may play vital role in not only identifying the etiology but also in preventing the iatrogenic transmission of genetic defects to offspring via advanced assisted conception techniques (Hamada et al. 2013).

Introduction of intracytoplasmic sperm injection (ICSI) has brought hope for men with severe male infertility and provided a chance for them to become biological fathers. ICSI and other assisted reproduction techniques require testicular spermatozoa to be extracted to fertilize oocytes. Sperm retrieval is conducted with testicular aspiration or biopsy for testicular sperm extraction (TESE). Despite the current use of TESE, reliable clinical and laboratory prognostic factors of sperm recovery are still absent. Currently, several prognostic factors such as testis size, follicle-stimulating hormone (FSH), inhibin beta, the etiology of infertility, and genetic alterations are utilized; however, the histological testicular pattern remains the best predictor of sperm retrieval, but is associated with an invasive procedure (Glina et al. 2005).

Measurement of follicle-stimulating hormone (FSH) levels has been used as a predictor of sperm recovery, but its use remains controversial. Inhibins, anti-Mullerian hormone (AMH), and activins are glycoproteins that are transforming growth factors (TGF). Plasma levels of inhibin fraction B and seminal levels of AMH can be used as predictive parameters for sperm recovery in NOA (Deffieux and Antoine 2003). Other tests include the genetic detection of chromosome alterations. Y-chromosome microdeletions have also been used as a prognostic factor for sperm recovery. This possibility is based on the absence of mature sperm in azoospermic men with AZFa and AZFb microdeletions who underwent sperm retrieval techniques. Fortunately, AZFc is the Y microdeletion most often found in azoospermic men (60 %), and sperm can be retrieved for these patients. Therefore, the presence of AZFa or AZFb is a negative predictive factor for sperm retrieval in azoospermic men (Shefi and Turek 2006). The following section describes recent attempts toward development of prognostic markers that predict sperm retrieval in azoospermic patients.