CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations

CAG repeat expansion in exon 1 of the androgen receptor (AR) gene has been reported to be associated with male infertility in some but not all populations. Until now, studies have not been carried out to examine this among Indian populations. For the first time, we have analyzed the CAG repeat motif in the AR gene in 280 men with azoospermia and in 201 men with normal fertility. The mean number of CAG repeats in the AR gene of men with azoospermia was 21.7 +/- 0.18, with a high incidence of repeat number 22. Among fertile-control men, the mean number of CAG repeats was 22.4 +/- 0.19, with a predominance of repeat number 23. The highest number of CAG repeats (32) was found with low frequency in both fertile and azoospermic groups. Comparison of fertile men and those with azoospermia on the basis of CAG repeats revealed that the number of CAG repeats in both groups were similar, as revealed with a paired t test (t = 0.04; P =.967). Expansion of the CAG repeat in the AR gene is therefore not associated with male infertility in Indian populations. This suggests that what is true for one population may not be true for other populations.     

CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia

Objectives. To determine whether the number of CAG repeats in the androgen receptor gene is enhanced in patients with idiopathic azoospermia.Methods. Using the polymerase chain reaction, the number of CAG repeats was assayed in 41 patients with idiopathic azoospermia and in 48 normozoospermic fertile men.Results. In the control group, the CAG repeat length ranged from 17 to 30 (mean 23.9 ± 2.9); in the azoospermic group, the CAG repeat length ranged from 20 to 34 (mean 26.5 ± 3.5). The difference between the two groups was statistically significant (P = 0.0013). None of the men in the control group had a CAG repeat length greater than 31; four of the azoospermic men had 34 CAG repeats.Conclusions. Results suggest that an increase in the number of CAG repeats in the androgen receptor gene to 31 or greater may be associated with the etiology of at least some cases of idiopathic azoospermia.     

中国特发性无精子症和少精子症患者雄激素受体基因CAG重复多态性研究

目的分析中国特发性无精子症和少精子症患者雄激素受体(AR)基因(CAG)n微卫星多态性并探讨该多态性与精子生成障碍发生的关系。方法应用PCR和变性聚丙烯酰胺凝胶电泳分析技术对52例少精子症患者和31例无精子症患者的外周血标本进行CAG重复数测定,分析该微卫星多态性和精子生成障碍发生的关系。结果少精子症患者组和无精子症患者组CAG重复数均数分别为22.19和22.13,CAG重复数≥28的百分率分别为1.9%和3.2%,比例逐渐升高。结论AR基因(CAG)n微卫星的CAG重复数在中国男性不育患者中呈现多态性,与精子生成障碍发生的关系有待进一步研究。     

Cytogenetic and molecular analysis of the Y chromosome: absence of a significant relationship between CAG repeat length in exon 1 of the androgen receptor gene and infertility in Indian men

The genetic basis of male infertility remains unclear in the majority of cases. Recent studies have indicated an association between microdeletions of the azoospermia factor a (AZFa)-AZFc regions of Yq and severe oligospermia or azoospermia. Increased (CAG)n repeat lengths in the androgen receptor (AR) gene have also been reported in infertile men. Therefore, in order to assess the prevalence of these genetic defects to male infertility, 183 men with non-obstructive azoospermia (n = 70), obstructive azoospermia (n = 33), severe oligospermia (n = 80) and 59 fertile men were examined cytogenetically and at molecular level for Yq deletions, microdeletions, and AR-CAG repeat lengths along with hormonal profiles [luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T)]. We used high resolution cytogenetics to detect chromosome deletions and multiplex polymerase chain reaction (PCR) involving 27 sequence-tagged site (STS) markers on Yq to determine the rate and extent of Yq microdeletions. PCR amplification with primers flanking exon 1 of AR gene was used to determine the AR-(CAG)n repeat lengths. Hormonal profiles (LH, FSH and T levels) were also analysed in infertile and fertile men. Testicular biopsies showed Sertoli cell only (SCO) morphology, maturation arrests (MA) and hypospermatogenesis. No chromosome aberrations were found in infertile men but there was a significant increase (p < 0.001) in the association of acrocentric chromosomes including the Y chromosome. Yq microdeletions were found in 16 non-obstructive azoospermic men (16 of 70; 22%) and seven severe oligospermic individuals (seven of 80; 8.7%) and most of them had deletions in the sY240 locus. No Yq microdeletions were detected in patients with obstructive azoospermia. No statistically significant difference in the mean length of CAG repeats in AR gene was observed between infertile and fertile men (22.2 +/- 1.5 and 21.5 +/- 1.4 respectively). No significant increase or decrease in levels of LH, FSH and T was observed in infertile and fertile men. In some infertile men, significantly elevated levels of FSH alone or in combination with LH were found to be indicative of failure of spermatogenesis and/or suggestive of testicular failure. Y-chromosome microdeletions contribute to infertility in some patients but no relationship could be established with the (CAG)n repeat lengths in exon 1 of the AR gene in infertile Indian men.     

CAG repeat length analysis and mutation screening of the androgen receptor gene in Japanese men with idiopathic azoospermia.

Because androgens are required for normal spermatogenesis, we are investigating abnormalities in the androgen receptor as a possible cause of impaired spermatogenesis in patients with idiopathic male infertility. The CAG repeat length in exon 1 and mutations of the androgen receptor gene were studied in 30 men with idiopathic azoospermia and in 51 fertile men. In men with azoospermia, plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were measured and testicular biopsies were performed. The CAG repeat length ranged from 19 to 30 (mean 23.4 +/- 2.9) and from 17 to 28 (mean 23.7 +/- 3.2) in men with azoospermia and in controls, respectively. There was no significant difference between the 2 groups. In men with azoospermia, the Johnsen testicular biopsy score negatively correlated with plasma FSH (P < .01). However, the Johnsen testicular biopsy score did not correlate with plasma LH and testosterone levels. The CAG repeat length did not correlate with the Johnsen testicular biopsy score, or with plasma concentrations of LH, FSH, and testosterone. No abnormalities in the androgen receptor gene were detected. These facts suggest that the CAG repeat length and alterations in the androgen receptor gene are not associated with the etiology of idiopathic azoospermia.     

CAG repeat length in androgen receptor gene and male infertility in Egyptian patients

The CAG repeat and its association with infertility has been debatable. Therefore, this study was planned to assess the distribution of CAG repeat expansion in Egyptian patients and to investigate its association with male infertility. Forty-five infertile men were eligible for the study in addition to 20 aged-matched fertile males as control. Semen analysis, scrotal sonography, assay of serum testosterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), and determination of the CAG repeat number within exon 1 of the androgen receptor (AR) gene were carried out. Statistically significant difference was found between infertile and control groups regarding sperm count, sperm motility, serum FSH level and CAG repeats (P < 0.05); statistically insignificant difference for the CAG repeats (P = 1.0) was found between oligozoospermic and asthenospermic groups; negative correlation was found between CAG repeat length and sperm count, and a positive correlation was found between CAG repeat length and serum FSH (P < 0.05). Our results validate the concept that long stretches of CAG repeat may be associated with lower AR function with derangement of sperm production, and this may contribute to male infertility in Egyptian men.     

No association of androgen receptor GGN repeat length polymorphism with infertility in Indian men

Androgens, acting through the androgen receptor (AR), play a role in secondary sexual differentiation from the prenatal stage to adulthood, including spermatogenesis. The AR gene has 2 polymorphic trinucleotide repeats (CAG and GGN) in exon 1. The CAG repeat length polymorphism has been well studied in a variety of medical conditions, including male infertility. Many of these studies have shown an association of the expanded CAG repeats with male infertility, although this is not true for all populations. The GGN repeat, in contrast, has been less thoroughly studied. Thus far, only 4 reports worldwide have analyzed the GGN repeat, alone or in combination with the CAG repeat, in male infertility cases. No such study has been undertaken on infertile Indian men. Therefore, we have analyzed AR-GGN repeats in a total of 595 Indian males, including 277 azoospemric, 97 oligozoospermic, and 21 oligoteratozoospermic cases, along with 200 normozoospermic controls. The analysis revealed no difference in the mean number or the range of the repeat between cases (mean = 21.51 repeats, range 15-26 repeats) and controls (mean 21.58 repeats, range 15-26 repeats). Furthermore, no difference was observed when azoospermic (mean = 21.53 repeats, range 15-26 repeats), oligozoospermic (mean = 21.46 repeats, range 15-26 repeats), and oligoteratozoospermic cases (mean = 21.48, range 19-26 repeats) were compared individually with the controls.     

Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth.

BACKGROUND: The androgen receptor (AR) gene has a polymorphic CAG microsatellite encoding variable-length glutamine repeats in the AR protein. The purpose of this study was to evaluate the association between the growth of benign prostatic hyperplasia (BPH) and the AR gene CAG repeat length. METHODS: We determined CAG repeat lengths in 176 BPH patients who underwent simple prostatectomy and in 41 control subjects without benign prostatic enlargement (non-BPE group). RESULTS: A statistically significant (P < 0.02) trend for large adenoma size with short CAG repeat length was found among the adenoma quartiles. CAG repeat length in the fourth quartile (large adenoma, 21.5 +/- 2.7) was significantly shorter than in the first quartile (small adenoma, 23.3 +/- 2.1, P < 0.02). It tended to be shorter than in the non-BPE group (23.1 +/- 2.4), but CAG repeat lengths in the entire BPH (22.4 +/- 2.5) and non-BPE groups did not significantly differ. The relative risk of large BPH (the fourth quartile) was 2.75 (95% confidence interval, 1.05-7.24; P < 0.05) on comparing CAG repeats of < or = 22-> or = 23. CONCLUSIONS: Shorter CAG alleles may be a genetic factor that promotes the growth of BPH.     

Androgen receptor gene CAG repeat polymorphism and breast cancer risk in Iranian women: a case-control study

We investigated the association between polymorphic expansion of trinucleotide CAG repeats in androgen receptor (AR) gene and breast cancer risk among Iranian women in a matched case-control study. There was a strong overall association between per CAG repeat increments in average repeat length and the risk of the malignancy [OR=3.56; 95% CI, 2.80-5.29]. Women carrying one or two alleles with [CAG]n repeat ≥22 units were at increased risk of breast cancer [OR=2.03; 95% CI, 1.56-2.6]. The risk was significantly increased in homozygous longer repeats, versus homozygous alleles <22. We observed reduced risk of developing the tumor in positive familial breast cancer subjects carrying repeats ≥22 and 23. Homozygosity for the longer [CAG]n repeats may be linked to the increased breast cancer risk. In contrast to previous reports, longer AR [CAG]n repeat alleles may decline the risk among women with a familial breast cancer.     

AR CAG repeat length is not associated with serum gonadal steroids and lipid levels in healthy men

Cardiovascular risk factors seem to be affected by androgens, which exert their action through the androgen receptor (AR). Androgenic action correlates inversely with a polymorphic CAG repeat region in the AR gene encoding for glutamine residues the length of which appears to influence high density lipoprotein (HDL) cholesterol levels. The aim of the study was to investigate the possible association between AR gene polymorphism and serum sex steroids and lipids. 170 healthy males, aged 22–59 years (mean 42 years), were included in the study. Anthropometrical as well as sociometrical parameters were recorded. Body fat content (BFC) (% fat mass) was measured by bioelectrical impedance. Serum lipids and total and free testosterone (T) and estradiol (E₂) levels were measured in each subject. AR gene CAG repeats length was determined. No significant correlation was found between the length of AR gene polyglutamine tract and the levels of gonadal steroids (total and free T, total and free E₂) or to the lipid levels (Triglycerides, total, HDL and LDL cholesterol). In addition, serum lipid levels were not significantly different in the lower compared to higher half of CAG repeats length distribution. On multiple regression analysis BFC was found to predict HDL-cholesterol and triglycerides were found to show, respectively, significant negative and positive correlation with body fat content. In conclusion, AR gene polymorphism may not predict sex steroid levels in healthy males. Possible impact of CAG repeats length on lipids profile has not been established.     

Molecular analysis of CAG repeat length of the androgen receptor gene and Y chromosome microdeletions among Jordanian azoospermic infertile males

Assisted reproductive technology is a common procedure which helps millions of couples who suffer fertility problems worldwide every year. Screening for genetic abnormalities prior to such procedure is very important to prevent the transmission of harmful genetic mutations to future generations. Microdeletions within the azoospermia factor (AZF) region of the Y chromosome and the expansion of the CAG trinucleotides in the androgen receptor (AR) gene are among the susceptible causes of male infertility in different ethnic groups. Such association has never been studied in Jordan. In this study, we compared CAG repeat length between azoospermic infertile and normospermic fertile Jordanian males and we also screened the frequency of Y chromosome microdeletions in the same cohort. The study included 142 nonobstructive azoospermic cases and 145 normospermic controls. Results have shown that the median CAG repeat length in the azoospermic group is 19 ± 2 compared to 19 ± 1.5 (p = .6262) in the control group. Deletions within the Y chromosome AZF region were detected in 7 of 142 cases (4.93%) and no deletions were seen in the control group. The results of this study confirm the importance of the AZF region in normal spermatogenesis, whereas it shows no link between the length of CAG repeats in the AR gene and male azoospermia in Jordanian group examined.     

Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues

To investigate contraction of CAG repeats within the androgen receptor gene (AR) as shorter CAG repeats have been implicated as a possible risk factor in prostate cancer (PCa). AR CAG repeat lengths were analyzed in DNA from microdissected diseased prostates, leukocytes from matched peripheral blood, and control non-diseased prostates. Consistently, all prostatic tissues, whether from benign or cancerous areas of diseased prostates, or from control prostates, showed multiple AR CAG repeat contractions. Germline DNA from blood leukocytes had single CAG repeat lengths in the normal range. AR CAG repeat length contraction may be involved in prostate carcinogenesis and may precede the pathological process.     

Association of oestrogen receptor alpha polymorphisms and androgen receptor CAG trinucleotide repeats with male infertility: a study in 109 Greek infertile men

This study was performed to examine the contribution of genetic polymorphism of oestrogen and androgen receptor (AR) genes in male infertility. We have studied in total 173 Greek men, 109 infertile patients and 64 controls (group A). Patients were divided in to three subgroups: group B (n=29) with idiopathic moderate oligospermia, group C (n=42) with azoospermia or idiopathic severe oligospermia and group D (n=38) with azoospermia or oligospermia of various known aetiologies. All patients and controls were genotyped for two polymorphisms of the oestrogen receptor alpha (ERalpha) gene and also for the (CAG)n repeat length polymorphism of the X-linked androgen receptor (AR)gene. The control group had statistically significant difference from group C regarding the XbaI polymorphism of ERalpha gene. Despite the fact that we did not observe any statistically significant differences in the mean and range of the CAG repeat number, the frequency of the higher repeats of the nucleotide repeat sequence (CAG)n of the AR gene was 2-4 times higher in groups B and C compared with the control group A. Our results indicate that both ERalpha and AR gene play significant role in male fertility. It is possible that a synergy may exist between unfavourable genotypes of these two genes in male infertility.     

Linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in the African-American population

African-American men are at an increased risk of developing prostate cancer when compared with other racial and ethnic groups. In addition, African-Americans display a greater propensity for developing aggressive prostate cancer. There are multiple etiologic factors that likely contribute to the development of prostate cancer; however, one potential factor that may explain differences of prostate cancer risk among ethnic and racial groups is the androgen receptor (AR) gene. Studies have showed that there is correlation between two polymorphic microsatellite regions of the AR receptor gene and its transactivational activity. The CAG and GGC repeats both have been implicated as important loci for variation in differential androgen receptor activity. This review analyzes the available data regarding variation of the CAG and GGC repeat sequences among different racial and ethnic populations, and the implications of these variations for prostate cancer risk.     

The association of androgen- and oestrogen-receptor gene polymorphisms with urolithiasis in men

OBJECTIVE: To evaluate the association of urolithiasis with polymorphic microsatellite (encoding cytosine, adenine, and guanine, CAG) repeats in the exon 1 region of the androgen receptor (AR) gene and thymine/adenine (TA) repeats in the oestrogen receptor (ER). PATIENTS AND METHODS: Patients with urolithiasis (149) and a group of normal controls (102) were examined and compared. The CAG repeats of the AR gene and TA repeats of the ER gene were detected by polymerase chain reaction. The CAG repeats ranged from 171 bp (10 CAG repeats with 141 bp of amplified flanking sequences) to 270 bp (43 CAG repeats). The TA repeats ranged from 160 bp to 194 bp. Associations between calcium oxalate stone disease and the CAG repeats in AR gene and TA repeats in ER gene were then evaluated. The results were classified according to sex and peaks in allelic frequency distribution. RESULTS: There was a significant difference between the male stone patients and the normal controls in the distribution of CAG repeats in the AR gene. Both groups showed a high percentage of 21-repeats in the allelic distribution, at 17 (16%) and 20 (37%) in stone patients and normal controls, respectively. The results indicate that 21-CAG repeats might be related to a lower risk of stone formation in men (P < 0.05). In the ER gene, the peak allelic distribution of TA repeats was 14, showing a significant difference between male stone patients and the normal control subjects (P < 0.01). There were no statistical differences between female stone patients and the control subjects in either the AR or the ER gene. CONCLUSION: Urolithiasis among men appears to be associated with AR gene CAG repeat and ER gene TA repeat polymorphisms, whereas there was no significant association among female stone patients. These sex hormone receptors seem to be related to the higher incidence of stone formation among men.