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From the * Instituto de Ciencias en
Reproducción Humana Vida (Instituto Vida), León, Guanajuato,
México; and the Facultad de Medicina,
Benemérita Universidad Autónoma de Puebla, México.
| Correspondence to: Sandra Guadalupe Martínez-Garza, Instituto de Ciencias en Reproducción Humana Vida (Instituto Vida), Plaza Las Américas 115, Col Jardines del Moral, León, Guanajuato, México, CP 37160 (e-mail: samartin30{at}yahoo.com). |
| Received for publication October 2, 2007; accepted for publication July 3, 2008. |
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Abstract |
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Key words: Oligospermia, karyotype, microdeletion, trinucleotide repeat
Azoospermia factor (AZF) is a region in the Y chromosome that encodes genes necessary for normal spermatogenesis. Small deletions in this region can be detected using molecular biology techniques (for example, analyzing STS [sequence-tagged site] markers). Extensive physical, functional, and genetic analyses of the Y chromosome have identified 3 AZF regions (AZFa, AZFb, and AZFc) that encode spermatogenic genes such as USP9Y, RBMY1, BPY2 and DAZ (deleted in azoospermia; Vogt, 1997). The refinement of Yq mapping and the availability of a complete Y chromosome DNA sequence (Skaletsky et al, 2003) allows the emergence of a new classification of Y chromosome deletions, which are used for clinical diagnostic purposes: AZFa, AZFb (P5/proximal P1), AZFbc (P5/distal P1 or P4/distal P1), and AZFc (b2/b4; Simoni et al, 2004). Several groups found Y microdeletions in azoospermic and oligozoospermic patients with an incidence range of 7%–21% and 0%–14%, respectively (Najmabadi et al, 1996; Silber et al, 1998; Kim et al, 1999; Foresta et al, 2001). Although genotype-phenotype correlations have been difficult to establish, multiple studies support the idea that Y microdeletions are a common cause of spermatogenic failure. Complete deletions of AZFb and AZFb,c (P5/proximal P1, P5/distal P1, P4/distal P1) are characterized by a histologic picture of Sertoli cell only (SCO) or spermatogenetic arrest resulting in azoospermia (Simoni et al, 2004). In oligozoospermic patients, AZFc deletions had been associated with a decline in sperm production over time (Girardi et al, 1997; Simoni et al, 1997). In general, AZFc deletions are compatible with residual spermatogenesis. AZFc deletions can be found in men with azoospermia or severe oligozoospermia (Simoni et al, 2004). Detection of Yq microdeletions is very important, not only to define the cause of spermatogenic failure, but also because these patients need genetic counseling since this chromosome defect can be transmitted to 100% of the male offspring.
It is well-known that androgens determine male sexual differentiation and also promote the initiation and maintenance of spermatogenesis. Androgens act on target cells through the androgen receptor (AR). The AR gene is located in the X chromosome at Xq11-1. The AR gene has 8 exons that encode 3 protein domains: Transactivation domain (exon 1), DNA-binding domain (exons 2 and 3), and ligand-binding domains (exons 4–8). Exon 1 contains a polymorphic CAG (glutamine) repeat sequence. The AR-CAG repeat region is unstable, and its length may sometimes undergo expansion or contraction during meiotic DNA replication. Mutations in the AR gene cause various degrees of androgen resistance, resulting in wide androgen insensitivity syndromes—from 46,XY sex-reversed infertile women to phenotypically normal 46,XY infertile males with severe oligozoospermia or azoospermia (Mifsud et al, 2001; Wallerand et al, 2001; Milatiner et al, 2004). In vitro studies have demonstrated a negative correlation between CAG repeat size and AR function, especially in terms of transcriptional activity (Chamberlain et al, 1994). There are some clinical studies showing that longer CAG repeats are associated with defective spermatogenesis (Komori et al, 1999; Mifsud et al, 2001; Wallerand et al, 2001; Mengual et al, 2003; Milatiner et al, 2004; Katagiri et al, 2006); however, other studies have failed to show a significant correlation (Dadze et al, 2000; Thangaraj et al, 2002; Asatiani et al, 2003; Ruhayel et al, 2004; Singh et al; 2006). Since this association may be dependent on the population studied and local environmental conditions, we aimed to study the CAG repeat size in the Mexican population and determine if it correlates with abnormal sperm counts.
In this work, we investigated chromosomal abnormalities, Y chromosome deletions, and androgen receptor CAG repeat length and their association with defective spermatogenesis in infertile Mexican men.
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Materials and Methods |
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15 x 106/mL) who were planning to undergo any assisted
reproductive technique due to male factor infertility. All cases of
azoospermia or oligozoospermia resulting from endocrine or obstructive causes
were excluded from our study. The control group consisted of 40 individuals
with normal semen analysis who were used as donors at our semen bank. All of
them had proven paternity. Only patients and controls born in Mexico and with
Mexican parents were included in this study. All were from the center of the
country and represent a homogenous group of mixed-race people called
"Mestizos." All participants gave informed consent according to
the protocol approved by the ethics review board. Peripheral blood samples
were drawn with heparin and EDTA and stored at 4°C until cell culture and
DNA isolation were done.
Cytogenetic Analysis
Chromosome analysis was performed on peripheral lymphocyte cultures.
Cultured cells were treated with colchicine to obtain prometaphase
chromosomes. The GTG banding technique was applied, and 20 metaphases were
counted in each patient and control.
Molecular Analysis
DNA isolation was performed using TSNT lysis buffer (1% Triton, 1% SDS, 100
mM NaCl, 10 mM Tris-HCl (pH 8.0), and 1 mM EDTA) followed by phenol-chloroform
extraction. DNA was diluted and stored at 4°C before analysis.
The Y Chromosome Deletion Detection System, version 1.1 (Cat. No. MD1101; Promega, Madison, Wisconsin) kit was used to determine the presence or absence of 18 STS by performing 4 PCR amplifications. Commercial protocols were followed to perform PCR and electrophoresis. Multiplex PCRs were repeated to confirm the results whenever a deletion was found. This kit analyzed AZFb (SY121, SYPR3, SY124, SY127, SY128, SY130, SY133) and AZFc (SY145, SY153, SY152, SY242, SY259, SY208, SY254, SY255, SY157). We also decided to use SY84 and SY86 to analyze AZFa, and SY134 to analyze the complete AZFb according to Simoni (Simoni et al, 2004).
CAG repeats in exon 1 of the AR gene were generated as described by Dadze
et al, with some modifications (Dadze et
al, 2000), and only patients with normal cytogenetic analysis and
without microdeletions were analyzed. One hundred nanograms of DNA was used in
a single 15 µl PCR containing 1x PCR buffer, 0.2 mM of each dNTP, 1.5
mM MgCl2, 0.5 U Taq DNA polymerase (Promega), 0.2 µM of each
AR-1/AR-2 primer (Invitrogen, Carlsbad, California). PCR conditions were an
initial denaturation step at 95°C for 5 minutes, followed by 30 cycles of
denaturation at 95°C for 45 seconds and annealing at 68°C for 90
seconds. A final step of extension at 68°C for 5 minutes was added. PCR
products were electrophoresed through a 2% agarose gel to confirm
amplification. PCR products were mixed with an equal amount of loading buffer,
denatured at 95°C for 4 minutes, and put on ice before loading. Denatured
reactions were separated on a 6% urea-polyacrylamide gel with 0.5x TBE
at 250 V for 
10 hours, followed by silver staining. The size of the PCR
band was determined by comparing the size of this band with the size of
sequenced PCR products containing CAG repeats of known length, which were
kindly donated by Dr M. Aevizaki. Quantity One Quantitation Software (Bio-Rad,
Hercules, California) was used to determine the size of PCR products.
Statistical Analysis
Unless otherwise stated, results are reported as mean ± SD.
Statistical differences between 2 means were obtained using the Student's
2-tailed unpaired t test. For multiple comparisons, 1-way analysis of
variance was used. Data were considered statistically significant when
P < .05.
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Results |
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Cytogenetic Evaluation— Chromosome analysis was performed analyzing 20 metaphases for each patient and control. No chromosome abnormalities were detected in controls, and 9 [11% (CI, 4.2–17.8)] abnormalities were identified in infertile males (Table 3). Eight out of 9 aberrations were detected among azoospermic men: Five were 47,XXY; one was 47,XYY; one was 46,XY,Yq-, and one was 46,XY inv (9). The frequency of chromosome abnormalities in azoospermic patients was 16% (8/50). One severe oligozoospermic man out of 28 (3.6%) presented an abnormal karyotype [46,XY, t(1;15)Lq(12;q25)].
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Y Chromosome Microdeletion Screening— All 122 males were screened for the presence of microdeletions in the Y chromosome. No microdeletions were identified in any of the control males. Microdeletions were found in 10 of 82 (12.2%; CI 5.1–19.3) infertile males (Table 3; Figure 1). The frequency of microdeletions was 12% (6/50) in the azoospermic group and 14.3% (4/28; CI 1.3–27.3) in the severe oligozoospermic group. Seventy percent of the infertile patients had microdeletions in the AZFc region (b2/b4; 3 azoospermic and 4 severe oligozoospermic males), 20% (2 azoospermic males) in the AZFb region, and 1 azoospermic male (10%) in the AZFb,c regions. No deletions in the AZFa region were detected. The larger microdeletion involving 2 complete AZF regions (b and c) was detected in an azoospermic male, and this finding was observed in his karyotype (46XY,Yq-). Also, one patient presented both a microdeletion and an abnormal karyotype [46,XY,inv(9)].
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Discussion |
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Our findings support the previous notion that abnormalities in sex chromosomes are primarily involved in azoospermic patients, while balanced autosomal anomalies are the most frequent in oligozoospermic males (Elghezal et al, 2006).
The association between Yq microdeletions and PSF has been reported since the 1990s. Even though there are considerable variations in the frequencies reported, it appears that the mean is 7.6% in patients with PSF (Krausz et al, 2003). In our population, the frequency of microdeletions in the severe oligozoospermic group is 14.3%, which is higher than the 12.2% in the azoospermic group. However, these frequencies are similar to previous reports (Najmabadi et al, 1996; Silber et al, 1998; Kim et al, 1999; Foresta et al, 2001; Simoni et al, 2004).
In this study, AZFa was not deleted, and the AZFc region was the most frequently deleted (70%) followed by the AZFb region (20%) and AZFb,c (10%). These data are in agreement with the literature, in which the most commonly affected region reported is AZFc (Hopps et al, 2003; Simoni et al, 2004). We found that deletions of the AZFc region were all b2/b4, and the phenotype of these patients was heterogeneous because 3 patients were azoospermic and 4 were severely oligozoospermic. These results are similar to those in which a variable clinical and histologic phenotype have been found (Reijo et al, 1996; Oates et al, 2002).
AZFb deletions were found in 2 azoospermic patients: Patient 2 is missing only sy128, while Patient 15 is missing both sy121 and sy128. Both patients had amplified sy127 and sy134, indicating that the AZFb deletions are partial. However, with the methodology used it is not possible to determine if the deletions correspond to the P5/proximal P1 pattern.
Complete AZFb,c deletion was also found in an azoospermic patient. This deletion was indicated by the lack of amplification of sy127, sy134, sy254, and sy255; however, because of the methodology employed, we were not able to identify P5/distalP1 or P4/distal P1 patterns.
These findings help us to realize that the frequency of Yq microdeletions in Mexican infertile males are similar to that in other populations studied (Table 5).
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The role played by androgens in spermatogenesis regulation is well-established. Groups from Spain (Mengual et al, 2003), France (Wallerand et al, 2001), the United States and Singapore (Mifsud et al, 2001), and Japan (Komori et al, 1999) found an association between longer CAG repeats and low sperm count, while studies from Germany (Dadze et al, 2000; Asatiani et al, 2003), India (Thangaraj et al, 2002), and Israel (Milatiner et al, 2004) have not shown a significant correlation. A recent meta-analysis (Davis-Dao et al, 2007) using 33 published studies found an association of CAG repeat length in AR and male infertility; the mean difference (95% confidence interval) was 0.19 (0.09–0.29) and 0.31 (0.14–0.47) for cases and controls, respectively; for a subset of 13 studies with more stringent case and control criteria. It seems that this association varies according to patient ethnicity; however, statistically significant differences were not found in Davis-Dao et al (2007), which used stratified analysis for race/ethnicity.
Our study investigated the association between the number of CAG repeats and sperm counts in infertile Mexican males. In this context it is necessary to clarify the Mexican ethnicity from a genomic point of view. Cerda-Flores et al (2002) revealed that Mexicans are represented by Mestizos resulting from an admixture of Amerindians, Spaniards, and, to a lesser extent, African populations, giving a unique genetic component. Around 65% of the Mexican genetic background can be classified as "Amerindian," the result of a mixture of 35 ethnic groups (unpublished observations). This preliminary finding shows the importance of our infertility results from an ethnical point of view and warrants further investigation in genetic particularities of male infertility in Latino populations.
In our study, Mexican men were first screened for genetic chromosomal aberrations and Yq microdeletions to eliminate genetic factors known to be correlated with infertility. We found no differences in the mean number of CAG repeats between infertile men (21.6 ± 3.39; range, 11–35) and controls (20.88 ± 3.19; range, 10–28). The infertile group was further subdivided according to sperm counts, and no differences were found in any subgroup when compared to controls. These results are in agreement with studies in which no association was found.
In conclusion, our study shows that genetic abnormalities and Yq microdeletions in infertile Mexican patients are frequent and similar to those reported in other countries. We found no difference in CAG repeats between patients with PSF and normal sperm donors; accordingly, we did not find a correlation between CAG repeats and sperm count. We suggest that genetic chromosomal abnormalities and Yq microdeletions be analyzed in all patients who undergo any assisted reproductive technique.
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Acknowledgments |
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