雄激素受体基因CAG多态性对男性激素避孕有效性影响的研究

目的：分析应用肌注十一酸睾酮酯（TU）进行激素避孕的男性志愿者中起反应者与不起反应者雄激素受体（AR）基因（CAG）n微卫星多态性，并探讨该多态性对激素避孕效果的影响。方法：29例TU不起反应者和34例起反应者分别作为试验组和对照组，应用PCR和DNA测序技术对两组外周血标本进行CAG重复数测定，分析该微卫星多态性对激素避孕效果的影响。结果：试验组和对照组CAG重复数的均数分别为23．62和22．97，均数比较差异无显著性（P〉0．05）。短组CAG（n≤22）在试验组和对照组的分布分别为51．7％、50．0％；长组CAG（n〉22）在试验组和对照组分布分别为48．3％、50．0％，长短组分布相同。CAG重复数与精子密度之间未见相关性。在FSH浓度〉0．2IU／L组中，CAG重复数〉22的受试者达到无精子症的机会是其他受试者的1．5倍。结论：受试者AR基因（CAG）n重复数呈多态性，但不反应组与反应组之间不具有显著性差异，AR基因CAG重复数或其他因素与男性激素避孕效果之间的关系有待进一步探讨。     

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。     

雄激素受体基因CAG重复多态性与男性不育关系的Meta分析

目的:采用Meta分析系统评价雄激素受体(AR)基因CAG串联重复多态性与男性不育的关系。方法:检索Medline、CBM等数据库中有关AR基因CAG重复数与男性不育相关性的病例对照研究,并用RevMan4.2软件进行统计分析。结果:共纳入32篇符合条件的文献,累计特发性不育病例3153例、对照2314例。数据合并结果显示,男性不育、无精子症及中度少精子症者其CAG重复数均数均显著高于对照人群(P<0.01),三者与对照间CAG重复数均数的标准均数差分别为0.27,95%CI:0.17～0.37;0.29,95%CI:0.08～0.50;0.27,95%CI:0.13～0.41。而且,敏感性分析结果也与以上研究结果一致。结论:AR基因CAG重复多态性其重复数增多与精子发生障碍的风险相关。     

雄激素受体基因CAG多态性与迟发性性腺功能减退症的相关性研究

目的:研究雄激素受体基因(AR)重复序列(CAG)n多态性与迟发性性腺功能减退症(LOH)的关系,探讨LOH的发病机制。方法:共调查1 000例40～70岁中老年男性,其中19例迟发性性腺功能减退症患者,随机抽取127例正常健康中老年男性,测定甘油三酯(TG)、空腹血糖(FBG)、血清总睾酮(TT)、游离睾酮(fT),测量身高、体重、腰围(WC)、血压,并采用DNA测序方法进行AR基因外显子1氨基端转录调节区(CAG)n重复序列长度测定,比较两组各指标之间的差异。结果:(CAG)n重复次数为15～32(23.05±2.95)。正常健康中老年男性的体重指数(BMI)、FBG较LOH患者显著下降(P<0.01),而TG、TT及fT较LOH患者显著升高(P<0.01)。正常健康中老年男性AR基因(CAG)n重复数为22.54±3.06;LOH患者AR基因(CAG)n重复数为23.23±2.24;LOH患者(CAG)n重复数略高于正常健康人群,但两者比较无统计学意义(P=0.946)。(CAG)n重复长度显示:长组(n≥22)AR基因(CAG)n在LOH组和正常健康中老年男性组的频率分别为73.68%和48.82%(P<0.05)。相关分析显示:TT、fT与(CAG)n重复序列无明显相关性(r=0.04和r=0.025,P>0.05)。结论:LOH男性AR基因(CAG)n重复序列呈现多态性,长(CAG)n重复多态可能是LOH发病的遗传因素,但仍需进一步扩大样本量证实。     

前列腺癌与雄激素受体基因(CAG)n重复多态性的关系

目的　探讨前列腺癌 (PC)与雄激素受体 (AR)基因 (CAG)n重复多态性的关系。　方法　应用DNA双链循环测序方法对 34例PC组织与癌旁正常组织、2例PC患者外周血白细胞内的AR基因 (CAG)n重复数进行测定。　结果　同一PC患者的癌组织与癌旁正常组织 (CAG)n重复数相同 ;36例患者癌组织AR基因 (CAG)n呈重复多态性 ,平均 2 0 .0 6 ,显著低于正常组织 ,差别有显著性意义 (P <0 .0 5 ) ;不同分化程度的癌组织 (CAG)n重复数差别无显著性意义 (P >0 .0 5 )。　结论　AR基因 (CAG)n重复数改变的体细胞突变在PC癌细胞中罕见 ,该重复数的减少可能与PC发病相关     

雄激素受体基因中(CAG)n微卫星多态性与原发性肝癌

雄激素受体(AR)基因第一外显子中含有遗传多态性的(CAG)n微卫星序列,此序列与多种疾病的发生、发展密切相关.本文就国内外AR(CAG)n微卫星多态性与原发性肝癌的关系研究的最新进展作一概述.     

无精或严重少弱精症与雄激素受体基因重复多态性的关系

目的探讨无精或严重少弱精症患者与雄激素受体基因(CAG)n重复多态性的关系。方法应用DNA双链循环测序方法,对32例无精或严重少弱精症患者(不育组)、15例正常生育男性(对照组),进行外周血雄激素受体基因(CAG)n重复数的测定。结果不育组32例患者(CAG)n重复数为17~25,平均21.08±2.1;对照组15例为11~27,平均21.2±2.3。两者比较差异无统计学意义。结论无精或严重少弱精症患者与雄激素受体基因(CAG)n重复数的没有关系。     

雄激素受体基因CAG多态性对男性生殖系统疾病的影响

众所周知，雄激素通过和雄激素受体的结合来调控雄性的发育分化及维持正常的性功能。在雄激素受体的N端，也就是转录活性区域存在着多聚谷氨酰胺【(Gln)n】和多聚甘氨酸【(Gly)n】片段，两者分别由AR基因第一外显子中多态性微卫星序列(CAG)n和(GGC)n编码。(CAG)n重复序列在正常人群中一般为8～35，高于或者低于此范围会引发雄激素受体基因的异常表达，从而诱发脊髓延髓肌萎缩症、Huntington舞蹈病、脊髓共济失调、纯痉挛性截瘫、脆性X染色体综合征、前列腺癌、特发性少(无)精子症等多种疾病。     

中国人群雄激素受体基因CAG多态性与前列腺癌关系的研究

目的　探讨国人雄激素受体 (AR)基因CAG多态性分布及与前列腺癌的关系。　方法　采用PCR、DHPLC和直接测序方法 ,对 10 5例前列腺癌和 190例健康老年男性外周血标本进行AR基因CAG重复长度测定 ,分析评价CAG重复长度与前列腺癌易感性的关系。　结果　前列腺癌和对照组ARCAG平均重复长度分别为 2 2 .7和 2 3 .3 ,差异无显著性意义 (P =0 .2 2 )。CAG重复长度<2 2与≥ 2 2相比 ,患前列腺癌的危险性增加 2 .3 9倍 ,差异有显著性意义 (P =0 .0 12 )。　结论　中国男性人群AR基因短的CAG重复长度 (<2 2 )与前列腺癌的危险性有关。与西方人群研究结果相比 ,中国男性有长的CAG重复     

前列腺癌患者雄激素受体N端AF1区的突变研究

目的　探讨雄激素受体 (AR)N端转录活化功能区 (AF1)突变与进展的关系。　方法采用PCR SSCP(单链构象多态性 ) DNA双链循环测序法对 2 7例前列腺癌 (PC)石蜡切片组织的ARN端AF1区突变进行检测 ,用DNA测序法确定PC组织AR基因外显子A中的CAG重复数目[(CAG)n]。　结果　在ARN端的AF1区证实了 2种错义突变 (Gly142Val和Asp2 2 1His) ,均存在于低分化的PC组织。 2例突变AR基因外显子A的 (CAG)n均为 17。　结论　在国人PC组织ARN端AF1区发现了 2种新的AR基因突变型 ,突变AR的 (CAG)n重复数目均低于平均水平 ,提示AR突变可能与PC进展有关     

Evidence for association of sex hormone-binding globulin and androgen receptor genes with semen quality

The roles of androgen receptor AR(CAG)n gene polymorphisms and sex hormone-binding globulin SHBG(TAAAA)n gene polymorphisms on semen quality were studied. One hundred fourteen men were included in the study: 85 with normal sperm count and 29 oligospermic. The genotype analysis, on DNA extracted from spermatozoa, revealed five SHBG(TAAAA)n alleles with 6–10 repeats and 18 AR(CAG)n alleles with 12–32 repeats. The SHBG allelic distribution showed that in men with normal sperm count and motility, those with short SHBG alleles had higher sperm concentration than men with long SHBG alleles ( P  = 0.039). As concerns AR(CAG)n polymorphisms, men with short AR alleles had lower sperm motility compared to those with long AR alleles ( P  < 0.001) in both total study population and normal sperm count men. The synergistic effect analysis of the two polymorphisms revealed an association between sperm motility ( P  = 0.036), because of the effect of AR(CAG)n polymorphism on sperm motility. In conclusion, long AR alleles were found to be associated with higher sperm motility, while short SHBG alleles were associated with higher sperm concentration, supporting the significance of these genes in spermatogenesis and semen quality.     

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.     

Polymorphic repeats in the androgen receptor gene in high-risk sibships

BACKGROUND: Genetic susceptibility may explain some familial clusters of prostate cancer. The polymorphic androgen receptor (AR) gene, which mediates androgen activity in the prostate, is a candidate gene that may influence predisposition to the disease. METHODS: We analyzed the polymorphic (CAG)n and (GGN)n repeats within the AR gene in men from 51 high-risk prostate cancer sibships, which included at least one affected and one unaffected man (n = 210). We compared repeat lengths of men with prostate cancer (n = 140) to their brothers (n = 70) without disease, stratified by median age at diagnosis of affected men within each sibship. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals to evaluate associations between prostate cancer and repeat length. RESULTS: The OR for prostate cancer associated with short (CAG)n repeats (< 22) compared to longer repeats (> or =22) was 1.13 (95% CI 0.5-2.4) overall, but was higher in sibships with a median age of <66 years at diagnosis (OR = 1.72, 95% CI 0.5-6.0). The (GGN)n array also was not associated with prostate cancer in general. However, in older men (> or = 66 years), there was a modest elevation in risk (OR = 1.56, 95% CI 0.6-4.1) among those with short repeats (GGN of < or =16). Men with both a short (CAG)n (< 22) and a short (GGN)n (< or =16) array were not at higher risk (OR = 1.06) compared to men with two long repeats [(CAG)n > or =22 and (GGN)n >16)]. CONCLUSIONS: These results suggest that the (CAG)n and (GGN)n repeats in the AR gene do not play a major role in familial prostate cancer.     

Androgen receptor gene polymorphisms and the fat-bone axis in young men and women

Androgen receptor (AR) CAG(n) (polyglutamine) and GGN(n) (polyglycine) repeat polymorphisms determine part of the androgenic effect and may influence adiposity. The association of fat mass, and its regional distribution, with the AR CAG(n) and GGN(n) polymorphisms was studied in 319 and 78 physically active nonsmoker men and women (mean ± SD: 28.3 ± 7.6 and 24.8 ± 6.2 years old, respectively). The length of CAG and GGN repeats was determined by polymerase chain reaction and fragment analysis, and confirmed by DNA sequencing of selected samples. Men were grouped as CAG short (CAG(S)) if harboring repeat lengths ≤ 21, the rest as CAG long (CAG(L)). The corresponding cutoff CAG number for women was 22. GGN was considered short (GGN(S)) if GGN ≤ 23, the rest as GGN long (GGN(L)). No association between AR polymorphisms and adiposity or the hormonal variables was observed in men. Neither was there a difference in the studied variables between men harboring CAG(L) + GGN(L),CAG(S) + GGN(S),CAG(S) + GGN(L), and CAG(L) + GGN(S) combinations. However, in women, GGN(n) was linearly related to the percentage of body fat (r = 0.30, P < .05), the percentage of fat in the trunk (r = 0.28, P < .05), serum leptin concentration (r = 0.40, P < .05), and serum osteocalcin concentration (r = 0.32, P < .05). In men, free testosterone was inversely associated with adiposity and serum leptin concentration, and positively with osteocalcin, even after accounting for differences in CAG(n), GGN(n), or both. In summary, this study shows that the AR repeat polymorphism has little influence on absolute and relative fat mass or its regional distribution in physically active men. In young women, GGN length is positively associated with adiposity, leptin, and osteocalcin.     

Predictors of pilosebaceous unit responsiveness to testosterone therapy in patients with hypogonadotrophic hypogonadism

Testosterone replacement therapy is the mainstay of treatment in male patients with isolated hypogonadotrophic hypogonadism (HH) to achieve virilisation. However, responsiveness of pilosebaceous unit (PSU) to testosterone replacement therapy in these patients is quite variable. Androgen action is inversely proportional to the number of CAG repeats in exon 1 of androgen receptor gene; therefore, we hypothesised that CAG repeat length contributes to testosterone responsiveness in patients with HH. The CAG repeat length in 21 well-virilised men (hair score > 30, responders) and 25 poorly virilised men (hair score ≤ 30, non-responders) with HH on optimal testosterone replacement therapy at least for a period of 1 year was analysed. Serum LH, FSH, testosterone and 17 β oestradiol were estimated. Polymerase chain reaction (PCR) amplification of exon 1 of androgen receptor gene was performed from genomic DNA, and these PCR-amplified products were sequenced for the number of CAG repeats. The difference between number of CAG repeats in responders and non-responders was statistically significant (19.19 ± 3.25 and 22.24 ± 2.65, P = 0.001) and showed a strong negative correlation with total body hair score (r = -0.538 and P = 0.0001). In conclusion, these results suggest that the number of CAG repeats influences the responsiveness of PSU to testosterone treatment in patients with HH.     

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.     

Androgen receptor polymorphisms and risk of biochemical failure among prostatectomy patients

BACKGROUND: Little is known about the role of inherited genotypes in prostate cancer (PC) progression. This prospective study evaluated the predictive value of androgen receptor (AR) polymorphisms (CAG and GGC repeats) among prostatectomy patients. METHODS: We studied 354 patients registered at M. D. Anderson Cancer Center from 1991 to 2001. Kaplan-Meier and Cox proportional hazard analyses were used. RESULTS: During an average follow-up of 56 months, 66 (19%) post-prostatectomy patients experienced biochemical failure (BF). Patients with higher CAG repeats (CAG > or = 24) had significantly longer BF-free survival (BFFS) than those with fewer repeats (CAG < or = 23) (P = 0.04). Higher CAG repeats were significantly associated with lower BF risk among Whites and African Americans. Among Whites, longer CAG repeats (relative risk (RR) = 0.45, P = 0.03) and Gleason score > or = 8 (RR = 19.33, P = 0.005) remained significant BFFS predictors in multivariate analysis. GGC repeats were not associated with BF. CONCLUSIONS: Our data showed that an inherited polymorphism (CAG repeats) in the AR is related to differences in genetic susceptibility to BF, supporting the hypothesis that increased AR activity may play a role in PC progression.     

Polymorphisms in the CYP19 and AR Genes—Relation to Bone Mass and Longitudinal Bone Changes in Postmenopausal Women With or Without Hormone Replacement Therapy: The Danish Osteoporosis Prevention Study

Polymorphisms in the androgen receptor ( AR) gene and genes encoding enzymes involved in synthesis of sex steroids (e.g., the CYP19 gene encoding aromatase) have recently received attention in osteoporosis research. In the Danish Osteoporosis Prevention Study, recent postmenopausal women were allocated to either hormone replacement therapy (HRT) or no treatment. We genotyped 1792 women for the CYP19 (TTTA)(n) repeat [short (TTTA)(n 7)] the CYP19 C(1558)-T, and the AR (CAG)(n) repeat polymorphism [short (CAG)(n < 22), long (CAG)(n >or= 22)], and investigated associations with bone mineral density (BMD) and 5-year change in BMD. The CYP19 polymorphisms were in strong linkage disequilibrium. Perimenopausal bone mass or bone loss in untreated women was not associated with the CYP19 polymorphisms. In hormone-treated women, BMD increase in the femoral neck was highest (+0.3%/year) for long CYP19 alleles, lowest (-0.09%/year) for short alleles, and intermediate (-0.002%/year) in heterozygous women, P = 0.015. Differences were also significant in the lumbar spine, total hip, and ultradistal forearm. The C(1558)-T T-allele was associated with a more pronounced response to HRT ( P = 0.04, total hip). AR genotype was not related to BMD, but a modifying effect of sex hormone-binding globulin (SHBG) was present. In the highest SHBG quartile (SHBG > 95 nmol/1, n = 222), AR genotype was associated with baseline BMD (femoral neck: P < 0.001, total hip: P = 0.008), but without a clear gene dosage effect. We have demonstrated that polymorphisms in the CYP19 gene are associated with the magnitude of bone gain in response to HRT and that the (CAG)(n) repeat polymorphism in the AR gene is associated with bone mass in women with high levels of SHBG. These findings emphasize the complexity of the genetics of bone mass and bone loss.