Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review

Evidence acquisition

Search strategy and selection criteria

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines.⁹ A comprehensive literature search of three different databases (PubMed, Scielo, and Science Directs) was performed using the following keywords: “Y-Chromosome” OR “Y-chromosome” AND “microdeletion,” AND “male infertility”. The keywords were the same for all databases. The search was limited to studies published within the last 10 years. The articles included in this review were selected based on the following predetermined inclusion criteria: (1) articles written in English, (2) articles that addressed the frequency of Y-chromosome microdeletion and male infertility, and (3) original studies with readily available full-text articles. On the other hand, the exclusion criteria included: (1) other type of articles including letters to the editor, reviews, and editorials; (2) articles that included patients with chromosomal abnormalities; and (3) articles that included patients who had undergone radiotherapy and chemotherapy. Duplicated manuscripts obtained from more than one database were counted as only one article.

Initial screening from titles and abstracts of the articles was done independently by two investigators (PB and IAD). The full texts of potentially relevant articles, or articles where no decision could be made from the abstract, were then reviewed. If there was any disagreement, the decision was made through discussion with other investigators (NR and WD). This search strategy yielded 141 results from the three above-mentioned databases, and three duplicated articles were automatically omitted. The abstracts of the remaining articles were screened to select the articles that were relevant to this review. As a result, 112 articles were excluded, leaving 26 articles for further investigation and evaluation of the full-text article. Finally, 12 studies were excluded, and 14 studies were found to be eligible for this review. The search strategy performed in this review is summarized in Figure 1.

Figure 1. Study flow diagram.

Quality assessment

The quality of each study was assessed using a tool developed by Hoy et al.¹⁰ to assess the risk of bias in prevalence studies. 10 domains were assessed based on internal and external validity of the studies: representativeness of the data, sampling methods, sample selection, likelihood of non-response bias, data collection, case definitions used, reliability and validity of the instruments, similarity of mode of data collection, length of prevalence period, and reliability of the calculations. Each domain was given a score of one (yes) or zero (no). Studies were classified as having low risk, moderate risk and high risk of bias if the overall score were >8, 6-8, and ≤5 respectively.

Data extraction

The data from the selected articles were then extracted independently by two authors (PB, IAS) using a standardized data extraction form that included the year of publication, authors, the number of patients with different types of Y-chromosome microdeletions, and the proportion of microdeletion in the major affected sub-regions of the Y-chromosome. Any discrepancy on the data extracted were solved by discussion and reference to the original article to meet the consensus.

Epidemiological aspects of Y-chromosome microdeletion

Approximately 10-15% of couples within reproductive age worldwide face infertility problems. Male infertility contributes to approximately 30-50% of these cases.¹ Y-chromosomal microdeletion is ranked second, after Klinefelter Syndrome, in the most common genetic causes of male infertility.⁶ Y-chromosome microdeletion affects testicular development greatly, phenotypically manifesting as azoospermia or oligozoospermia.⁴ The frequency of Y-chromosome microdeletion found in this review ranged from 1.7% to 23.9%. The high variability of Y-chromosome microdeletion among the different studies in this review mainly depended on the number of samples recruited in each study and the manner in which the samples were recruited. One study by Birowo P et al. in Indonesia reported the frequency of Y-chromosome microdeletion to be approximately 23.9% (17 out of 71 patients with non-obstructive azoospermia or severe oligozoospermia). Another study conducted by Saliminejad et al. in Iran showed that only 1.7% (2 out of 125) male infertility patients showed complete AZFc deletion. These two patients presented with non-obstructive azoospermia, while all other patients included in the oligozoospermia group in this particular study did not present with Y-chromosome microdeletions at all.¹⁶ Discrepancy in the frequency of Y-chromosome microdeletion was also observed in another study conducted by Totonchi et al. in a different institution in Iran. According to the results of this study, approximately 5.06% (185 out of 3654) infertile patients, enrolled from 2005 to 2011, were diagnosed with Y-chromosome microdeletion and a majority of the patients (74.96%) showed azoospermia.¹⁹ This discrepancy in Y-chromosome microdeletions was also observed among the studies conducted in different regions of China. For instance, Liu et al. conducted a retrospective study in southwestern China and found that 12.87% (185 out of 1274) infertile patients were diagnosed with Y-chromosome microdeletion.¹¹ Another comparably large study conducted by Dai et al. in northeastern China reported the frequency of Y-chromosome microdeletion to be 4.8% (58 out of 1200 patients). This clearly showed that variation in the frequency of Y-chromosome microdeletion was observed in not only different countries, but also different regions of a particular country.

Important affected sub-regions of the Y-chromosome

A 10-year cohort study conducted by Stahl et al. in North America showed that AZFc Y-chromosome microdeletions harbor the most common type of Y-chromosome microdeletions [78 out of 149 patients (52.3%)]. Patients diagnosed with this particular type of Y-chromosome microdeletion presented with various sperm concentration-related clinical manifestations ranging from oligozoospermia (3.8%) to severe oligozoospermia (32.1%) and azoospermia (64.2%). The other patients, who were mainly included in the azoospermia group [54 out of 55 patients (98.1%)], were diagnosed with other types of Y-chromosome microdeletions, including AZFa, AZFb, AZFbc, and complete Yq deletions.⁴ This finding that AZFc Y-chromosome microdeletions are the most commonly diagnosed Y-chromosome microdeletions with incidence ranging from 46.6% to 100% was concurrent with the findings of other studies conducted in Brazil, China, India, Iran, and Korea.^{11–13,22–24} However, one study conducted by Birowo et al. in Indonesia reported AZFa Y-chromosome microdeletions (64.7%), instead of AZFc Y-chromosome microdeletions, to be the most frequent type of deletion. The high prevalence of partial AZFa microdeletion (absent sY84, present sY86) could be attributed to the larger proportion of azoospermic patients recruited in this study (only 2 out of 17 patients presented with severe oligozoospermia). Additionally, it could be explained by the possibility of a single-nucleotide polymorphism (SNP), increasing the false positive results of AZFa microdeletions. This SNP, which is common in the Chinese ethnic group, includes a single-nucleotide conversion of T to G in the target sequence of the reverse sY84 primer (rs72609647). It can only be determined by sequencing the sY84 locus.^13,25

Clinical implications of Y-chromosome microdeletions

Y-chromosome microdeletion is one of the leading genetic causes of male infertility, greatly affecting testicular development.⁵ Birowo P et al. analyzed the testicular histology of two patients with partial AZFa deletion, one with AZFb deletion, and one with DBY gene exon 2 deletion. The testicular histology of the patient with AZFb deletion showed maturation arrest at the primary spermatocyte stage in all tubules, while that of the patient with DBY gene exon 2 deletion showed Sertoli cell only (SCO) syndrome. The testicular histology of the two patients with partial AZFa deletion indicated divergent spermatogenesis activity among the tubules. All four patients typically presented with azoospermia.¹³ Y-chromosome microdeletion evaluation also provides a deeper insight into the possibility of success of utilizing ART.^4,11,24 In general, AZFc deletion typically presents with various sperm concentration-related clinical manifestations ranging from oligozoospermia to azoospermia. Stahl et al. successfully exhibited a sperm retrieval rate as high as 71.4% in azoospermic patients with AZFc deletion by microTESE. However, no successful sperm retrieval was observed in the AZFa, AZFb, AZFbc, and AZFabc (Yq) deletion groups. Additionally, Liu et al. demonstrated that almost half (45.1%) the patients with AZFc deletion developed oligozoospermia, consequently indicating that a high sperm retrieval rate in these patients can be achieved by self-ejaculation instead of invasive surgical procedures. Furthermore, in terms of hormonal levels, younger oligozoospermic patients (21-30 years) with AZFc deletion typically exhibited higher testosterone and estradiol and lower follicle-stimulating hormone and luteinizing hormone expression levels.¹¹ This information allowed us to make an important finding that patients diagnosed with AZFc deletion showed higher chances of sperm retrieval for IVF/ICSI.

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.