Androgen Receptor Gene CAG Repeat Research Articles

Androgen Receptor Gene CAG Repeat Length Varies and Affects Semen Quality in an Ethnic-Specific Fashion in Young Men from Russia.

Male infertility is a multi-factorial and multi-genetic disorder, and the prevalence of male infertility in the world is estimated at 5–35%. The search for the causes of male infertility allowed for identifying a number of genetic factors including a single X-linked gene of the androgen receptor (AR), and some of its alleles are assumed to negatively affect male fertility. Our aim was (1) to study the variability of the length of CAG repeats of the AR gene and possible associations in the AR CAG genetic variants with semen quality and reproductive hormone levels in a population-based cohort of men and (2) to estimate distributions of AR CAG repeat alleles and associations with semen parameters in different ethnic subgroups. The cohort of 1324 young male volunteers of different ethnicities (median age 23.0 years) was recruited from the general population of five cities of the Russian Federation, regardless of their fertility status. Semen quality (sperm concentration, motility and morphology), reproductive hormone levels (testosterone, estradiol, LH, FSH and inhibin B) and trinucleotide (CAG) n repeat polymorphism in exon 1 of the AR gene were evaluated. The semen samples were analyzed according to the WHO laboratory manual (WHO, 2010), serum hormones were measured by enzyme immunoassay, and the AR CAG repeat length was analyzed by direct sequencing of leukocyte DNA. The median AR CAG repeat length in men of our multi-ethnic population was 23 (range 6–39). In the entire study population, a significant difference (p ≤ 0.05) was found in the frequency distribution and the mean values for the CAG repeat length between the groups with normal (23.2 ± 3.3) and impaired semen quality (23.9 ± 3.2). Additionally, we demonstrated that the total sperm count, sperm concentration, progressive motility and normal morphology were lower in the category of long CAG repeats (CAG ≥ 25) compared with those in the category of short CAG repeats (CAG ≤ 19); however, hormonal parameters did not differ between the long and short CAG categories, with the exception of estradiol. Significant differences were observed in the AR CAG repeat length between the most common ethnic cohorts of Slavs (Caucasians), Buryats (Asians), and Yakuts (Asians). The Buryats and Yakuts had a higher number of CAG repeats than the Slavs (medians: Slavs—23; Buryats—24; Yakuts—25). The range of alleles differed among ethnicities, with the Slavs having the largest range (7–36 repeats, 24 alleles total), the Yakuts having the smallest range (18–32 repeats, 14 alleles total) and the Buryats having the middle range (11–39 repeats, 20 alleles total). The longer CAG repeats were associated with an impaired semen quality within the Slavic (CAG ≥ 25) and Buryat (CAG ≥ 28) groups, but this effect was not found in Yakuts. Hormonal parameters did not differ between the three CAG repeat categories in men of all ethnic groups. This is the largest Russian study of the distribution of AR CAG repeats and the search for association between length of AR CAG repeat tract and impaired spermatogenesis in men from the general population. Our results confirmed the association of longer CAG repeats with a risk of impaired semen quality, but this association can be modified by ethnic origin. Identification of the number of AR CAG repeats can be an effective tool to assess the risk of male subfertility and the control of androgen hormone therapy of reproductive diseases.

Investigation of the relationship between Androgen Receptor Gene CAG Repeat Polymorphisms and Turkish gifted students’ science attitudes

This study aims to examine the AR gene CAG polymorphisms of gifted students, and to determine whether there is a relationship between this gene region and students' attitudes towards science. The research was conducted with randomly selected gifted students (N = 100) and normally developing students (N = 100) studying at the 5th grade level in Kocaeli, Turkey during the 2017-2018 and 2018-2019 school years. In order to determine students' attitudes towards science, science and technology lesson attitude scale was applied. According to the results of the study, while there was no significant difference in terms of "enjoyment" and "social content of science" from the science and technology lesson attitude scale factors, it was found that there was a statistically significant difference in favor of gifted students from the "scale total scores" and "desire to learn" factors (p<0,05). In the genetic dimension of the study, no statistically significant difference was found between the two groups in AR gene CAG polymorphisms. In the whole sample, there was no significant relationship between the AR gene CAG polymorphisms and the "scale total score" values.

The HEAT-Registry (HEmatopoietic Affection by Testosterone): comparison of a transdermal gel vs long-acting intramuscular testosterone undecanoate in hypogonadal men

Context Testosterone (T) therapy of hypogonadal men requires stable kinetics, tolerance and attenuation of symptoms. Both intramuscular injections of the long-acting ester T undecanoate (TU) and transdermal application of T gel offer a proven efficacy. As T has marked effects on hematopoiesis, an elevation of hematocrit has to be considered during T therapy. Objective To compare the effects of a transdermal T gel with long-acting intramuscular TU on hematopoiesis, controlling for age, diagnosis, androgen receptor susceptibility and obesity. Design Prospective two-arm open registry, minimum duration of 26 weeks per patient. Putative modulators of erythropoiesis entering regression models were type of medication, type of hypogonadism, delta of total testosterone concentrations, waist circumference, age as well as (in a sub-group) androgen receptor gene CAG repeat length. Setting Tertiary university based andrological outpatient department. Patients 802 hypogonadal men, 498 receiving T gel and 304 receiving intramuscular TU, median age 40 years (interquartile range = 25). Results Follow-up visits after initiation of treatment occurred between treatment weeks 26-30. Serum T concentrations increased markedly in both patient groups. Men receiving intramuscular TU exhibited an increased hematocrit (>50%) to a significantly higher amount than men receiving T gel (69/304 vs. 25/498, p < 0.001). Corresponding results were seen for higher values of hematocrit (>52% and >54%). Advanced age (p = 0.009), higher waist circumference (p = 0.01), higher delta testosterone (p = 0.007) and functional vs classical hypogonadism (p = 0.04) contributed to the effect in stepwise multiple regression models. Attenuated androgen action (longer androgen receptor CAG repeats) mitigated the effect (p = 0.01) in a subgroup of 574 patients. Men with anemia (hemoglobin ≤12.7 g/dl) were more likely to move out of the pathological range when receiving TU vs T gel (41/53 vs. 49/89 p = 0.01). Conclusions T substitution with intramuscular TU or T gel increase T concentrations effectively. Long-acting TU leads to a higher rate of hematocrit levels >50%, whilst at the same time it seems to be more efficient to ameliorate anemia in the subgroup of respectively affected hypogonadal patients . This applies especially to obese older men with functional hypogonadism.

Association of trinucleotide repeat polymorphisms CAG and GGC in exon 1 of the androgen receptor gene with male infertility: a cross-sectional study.

: Infertility is a global problem that brings about serious sexual and social consequences that strain the health sector and society. The expansion of CAG and GGC repeats in androgen receptor (AR) gene (Ensembl number ENSG00000169083) may lead to reduced fertility. Our objective was to determine the association of CAG and GGC repeats with altered sperm parameters in male infertile subjects. This was a cross-sectional study conducted at Aga Khan University, Karachi, Pakistan. A total of 376 males were recruited, out of which group A (N = 208) and group B (N = 168) were comprised of subjects with normal and altered sperm parameters, respectively, from 18 to 60 years. The numbers of CAG and GGC repeats were determined by using PCR amplification and sequence analysis using the Molecular Evolutionary Genetic Analysis (MEGA) software version 6.0. Statistical analysis was performed using the SPSS version 20 and the P-value of <0.05 was considered significant. The mean androgen receptor gene CAG repeats were significantly longer in males with altered sperm parameters as compared to male subjects with normal sperm parameters (P < 0.001). There was no significant difference found for GGC repeats for subjects with altered sperm parameters. Longer CAG length corresponded to greater severity of spermatogenic defect and may lead to subfertility recommendations.

Association of trinucleotide repeat polymorphisms CAG and GGC in exon 1 of the Androgen Receptor gene with male infertility: a cross-sectional study.

Infertility is a global problem that brings with serious sexual and social consequences that strain the health sector and society. The expansion of CAG & GGC repeats in androgen receptor (AR) gene Ensembl number; ENSG00000169083 may leads to reduced fertility. Our objective was to determine association of CAG and GGC repeats with altered sperm parameters in male infertile subjects. It was a cross sectional study conducted at Aga Khan University, Karachi Pakistan. A total of 376 males were recruited, out of which group A (N=208) and group B (N=168) comprised of subjects with normal and altered sperm parameters respectively from 18 to 60 years. Numbers of CAG and GGC repeats were determined by using PCR amplification and sequence analysis using Molecular Evolutionary Genetic Analysis (MEGA) software version 6.0. Statistical analysis was done using SPSS version 20 and p-value of < 0.05 were considered significant. The mean androgen receptor gene CAG repeats were significantly longer in males with altered sperm parameters as compared to male subjects with normal sperm parameters (p< 0.001). There was no significant difference found for GGC repeats for subjects with altered sperm parameters. Longer CAG length corresponded to greater severity of spermatogenic defect and may lead to subfertility recommendations.

Role of the Androgen Receptor Gene CAG Repeat Polymorphism on the Sequence of Pubertal Events and Adiposity in Girls with High Dehydroepiandrosterone Sulfate Level.

The androgen receptor (AR) harbors a variable repeat number of glutamine residues codified by (CAG)n, which seems to inversely affect AR transcriptional activity. We assessed whether (CAG)n affects the sequence of the androgen-sensitive pubertal events and body composition in prepubertal girls. Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (approximately 50% girls) from a university clinic in Santiago, Chile. Cases were girls with high dehydroepiandrosterone sulfate (DHEAS; >42μg/dL; HD) at age 7.0 (±0.4) years (n=58). On follow-up, 32 of them had thelarche (TB2) before the age of pubarche (PH2) and 26 had PH2 before the age of TB2. As controls, 107 age-matched girls with normal DHEAS (≤42μg/dL; ND) were selected. Methylation-weighted mean (CAG)n (mw[CAG]n) was calculated through X-chromosome methylation-sensitive enzyme restriction and polymerase chain reaction followed by automated capillary electrophoresis in peripheral blood DNA. Girls with HD and PH2 before the age of TB2 showed a trend to higher frequency (7/26, 26.9%) of mw(CAG)n <20 compared with ND girls (12/107; 11.2%; P=.087). Accordingly, a direct correlation between age of PH2 and mw(CAG)n was observed in HD (r=0.352; P=.007) and in ND girls (r=0.207; P=.033). Moreover, HD girls with mw(CAG)n less than 20 had lower waist circumference and waist/height ratio than HD girls with mw(CAG)n from 20 to less than 25 (P=.027 and P=.012, respectively) at age of DHEAS determination. Our results suggest that a greater transcriptional activity of theAR, given by short number of CAG repeats, might favor the onset of pubarche and reduce central adiposity in prepubertal girls with HD.

Interactive effects of testosterone and the androgen receptor CAG repeat length polymorphism on cardiovascular-renal events and mortality in men with diabetes.

Current evidence relating testosterone to cardiovascular disease and mortality is inconclusive. Cellular effects of testosterone are mediated by androgen receptor and longer receptor gene CAG repeat length correlates with reduced transcriptional activity. We investigated the independent and interactive association of total testosterone and CAG repeat length with incident cardiovascular disease (CVD), chronic kidney disease (CKD) and mortality in Chinese men with type 2 diabetes. From March 2008 and February 2009, 474 men with diabetes underwent structured clinical assessment including genotyping for CAG repeat length. Patients were followed for new-onset CVD, CKD defined by estimated glomerular filtration rate <60mL/min/1.73m2 , and death until 31 May 2015. In this cohort (mean age: 58.6years, disease duration: 15.4years), CAG repeat number ranged from 11 to 32 with median of 23, and 9.3% had low testosterone. Over follow-up of 5.8years, 49 (10.3%) men had CVD, 139 (29.3%) had CKD, and 43 (9.1%) died. In multivariate Cox regression adjusted for age, duration of diabetes, and cardiometabolic risk factors, both total testosterone and interaction term of total testosterone×CAG repeat were associated with all-cause death with respective hazard ratios 1.63 (P=0.002) and 0.98 (P=0.004). Total testosterone and CAG repeat were not related to incident CVD or CKD. Among men with type 2 diabetes, high total testosterone was associated with increased mortality in the presence of shorter CAG repeat length but decreased mortality in those with long CAG repeats.

Microsatellite variation of ESR1, ESR2, and AR in Serbian women with primary ovarian insufficiency

Objective: This study aimed to investigate the potential role of microsatellite polymorphisms of the estrogen receptor alpha gene (ESR1) TA repeat, estrogen receptor beta gene (ESR2) CA repeat, and androgen receptor gene (AR) CAG and GGN repeats among Serbian women with primary ovarian insufficiency (POI). These microsatellites have been reported to be associated with POI in different racial/ethnic populations.Methods: A cohort of 196 POI cases matched with 544 fertile controls was recruited by the Institute for Endocrinology, Diabetes and Metabolic Disorders of Serbia between 2007 and 2010. DNA was extracted from saliva. The four microsatellites were genotyped using a PCR-based assay to determine the repeat lengths.Results: POI patients carried shorter repeat lengths of ESR2 (CA)n than controls (P = 0.034), but the difference was small. ESR1 (TA)n was on the borderline of statistical differences between groups (P = 0.059). AR (CAG)n and (GGN)n showed no association with POI.Conclusions: We cautiously conclude that microsatellite polymorphisms of gonadal steroid receptor genes might contribute to the genetic basis of POI in Serbian women, but a larger-scale study and family-based studies are warranted to validate our findings even though the sample size in this study is larger than any previously published in this field.

A pharmacogenetic approach to improve low ovarian response: The role of CAG repeats length in the androgen receptor gene

The AR (androgen receptor) polymorphism is associated with POR risk. Furthermore, the use of androgens in POR remains controversial. Our data could clarify the effectiveness of androgen pretreatment. AR genotyping could help us to identify patients at risk for POR and POR patients that will be benefited of androgen pretreatment. ObjectiveThe aim of this project was to investigate if the AR (androgen receptor) polymorphism could be used to identify patients at risk for POR and that will benefit from androgens pretreatment. Study DesignTo evaluate the POR risk we performed a cohort study including 231 patients (54 POR and 177 control). Moreover, we included 88 IVF-cycles performed by 44 POR-patients to assess the effect on ovarian response. All patients performed two cycles: a standard ovarian stimulation and a second one with androgen preparation. We compare the results in pair from each. ResultsPOR showed the highest frequency of CAG repeats at 24 vs 22 in controls. Only 33% of POR have alleles with a repeat number below 23, compared with 50% of controls (p < 0.05). According to AR polymorphism ovarian response differences were shown. Patients that carried CAG repeats in AR gene between 22 and 24 showed an increased in the number of oocytes (2.61 in cycles without androgens vs 5.11 when they were pretreated with androgens; p < 0.05). For the patients that carried repeats lower than 22 and higher than 24, no differences were reported in the number of oocytes obtained in the cycle with or without androgens (2.94 vs 2.56; p = 0.88). Similar results were obtained for mature oocytes in patients that carry a number of CAG repeats between 22 and 24 (1.86 MII in cycles without androgens vs 4.04 MII when they were pretreated with androgens; p < 0.05). No differences in the number of MII oocytes were found in patients that get out of 22 and 24 repeats between the two cycles (2.31 vs 2.13; p = 0.88). ConclusionThe AR polymorphism is associated with POR risk, patients with repeats greater than 22 show a higher risk. Our data suggest that AR genotype could play a role in natural ovarian aging. Furthermore, the use of androgens in POR remains controversial. Our data suggest that the AR genotype could clarify the effectiveness of the androgen pretreatment. AR genotyping could help us to identify patients at risk of POR and POR patients that could benefit from transdermal testosterone pretreatment.

E relation between isolated micropenis in childhood with CAG and GGN repeat polymorphisms in the androgen receptor gene

Background/aim: In micropenis cases accompanied by external genital abnormalities such as hypospadias and cryptorchidism, infertility and spermatogenic failures have been reported to correlate with androgen receptor ( AR ) gene CAG and GGN repeat polymorphisms. While there is one study on isolated micropenis and CAG repeats, no study related to GGN repeats has been reported. We investigated the relation between CAG and GGN repeats in the AR gene with development of penis length in boys with isolated micropenis. Materials and methods: A total of 24 Turkish boys with isolated micropenis (<–2.5 SD) and 64 healthy controls who had normal basal serum gonadotropin levels were examined. Genotyping was performed by DNA sequencing of the patients and controls. Results: The distribution of CAG and GGN repeat lengths in our patients and controls was within the normal range and did not significantly differ between the patients and the controls. Conclusion: CAG repeat length in the AR constitutes one of multiple genetic factors relevant to the development of isolated micropenis, and the expansion of this repeat can be detected as a likely modifying factor. Moreover, the interactions of other genes that may be involved in the etiology of isolated micropenis with CAG and GGN repeats have to be taken into consideration.

102 Influence of Genetic Variation in the Androgen Receptor on the Risk of Cardiovascular Disease in Aging Men

Controversy still exists regarding the effect of hypogonadism on cardiovascular (CV) health and the safety of testosterone replacement therapy (TRT). We hypothesized that differences in androgen sensitivity, a function of the number of trinucleotide repeats on the androgen receptor (AR) gene, may result in greater reactivity to age-related testosterone changes and increased risk of CV disease. Participants were men from the Vietnam Era Twin Study of Aging (N=696). Mean age was 56.4 years (range:51-60). Average waking, salivary free-testosterone level was acquired on 3 non-consecutive days. Low testosterone (low-T) was defined as being ≥ 1 SD below the mean. The AR gene CAG repeat length was derived using polymerase chain reaction (PCR) fragment analysis and Sanger sequencing. Average repeat length was 22 (range:8-37). CV disease was assessed by self-report and medication data. We tested the interaction between low testosterone (low-T) and CAG repeat length while controlling for age, ethnicity, smoking status, BMI, hypertension, diabetes, and the correlated nature of the twin data.

Association of androgen receptor gene CAG and GGN repeat polymorphism with cryptorchidism: A meta-analysis.

Researches on association between variations in the androgen receptor (AR) gene repeat polymorphisms and cryptorchidism (CO) had conflicting results. The aim of this meta-analysis was to analyse the potential effects of AR CAG and/or GGN repeat polymorphism on CO. Studies were independently appraised by two investigators on PubMed, Web of Science, EBSCO databases and Foreign Medical Retrieval System. Case-control studies with measurement of CAG and/or GGN repeat length were included. Weighted mean difference (WMD) and 95% confidence intervals (CIs) for the CAG or GGN repeat polymorphism and CO were calculated. Five reports were included in this analysis. Overall, no difference was identified between patients and fertile men in CAG repeat length. However, when the CO was divided into unilateral and bilateral, longer CAG repeat region was significantly associated with CO in bilateral group (WMD=0.74; 95% CI, 0.01-1.47; p<.05). In addition, GGN lengths were significantly higher in patients compared with those in controls (WMD=1.17; 95% CI, 0.28-2.06; p<.05). No obvious effect was found in the GGN length when compared unilateral or bilateral group with control respectively. The results in this meta-analysis indicated that AR CAG and GGN repeat polymorphisms may be an important pathogenesis of CO.

MP91-13 THE ASSOCIATION BETWEEN TESTOSTERONE AND VITALITY: THE ROLE OF GENETIC VARIATION IN THE ANDROGEN RECEPTOR

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy I1 Apr 2017MP91-13 THE ASSOCIATION BETWEEN TESTOSTERONE AND VITALITY: THE ROLE OF GENETIC VARIATION IN THE ANDROGEN RECEPTOR Matthew Panizzon, Tung-Chin Hsieh, Franz Carol, Richard Hauger, and William Kremen Matthew PanizzonMatthew Panizzon More articles by this author , Tung-Chin HsiehTung-Chin Hsieh More articles by this author , Franz CarolFranz Carol More articles by this author , Richard HaugerRichard Hauger More articles by this author , and William KremenWilliam Kremen More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2853AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Controversy still exists regarding the efficacy of testosterone replacement therapy (TRT) for symptomatic hypogonadism. A recent multi-site randomized controlled study of men undergoing TRT failed to show an improvement in several symptom domains, among them is vitality. We hypothesized that differences in androgen sensitivity would obscure symptom improvement for a subset of individuals. Androgen sensitivity is related to the number of trinucleotide (CAG) repeats on exon 1 of the androgen receptor (AR) gene. We sought to examine the regulatory role of this genetic polymorphism on the relationship between testosterone and vitality in middle-aged men METHODS Participants were men from the Vietnam Era Twin Study of Aging (N=696). Average waking, salivary free-testosterone level was acquired on 3 non-consecutive days. The AR gene CAG repeat length was derived using a combination of PCR fragment analysis and Sanger sequencing. Vitality was evaluated with the SF-36Vitality scale. We tested the interaction between low testosterone (low-T) and CAG repeat length while controlling for age, ethnicity, smoking status, BMI, heart disease, hypertension, diabetes, and the correlated nature of the twin data. Low-T was defined as being = 1 SD below the mean for the 3-day average value RESULTS Mean age of the participants was 56.4 years (SD = 2.6) with average CAG repeat length of 22 (range: 8-37). We observed a significant interaction effect between low-T and AR CAG repeat length. In men with a short variant of the AR gene (< 21 repeats), representing greater androgen sensitivity, there was a significant effect of low-T on vitality (p < 0.01). Men with low-T and the short AR gene were on average 10 points lower on the Vitality scale relative to men with normal T and the same genotype. This effect was not observed in men with either medium (21-23 repeats) or long (= 24 repeats) variants of the AR gene. Without the interaction effect in the model, neither low-T nor the AR gene had a significant effect on vitality CONCLUSIONS These results demonstrate that the relationship between low-T and vitality is regulated, in part, by variation in the AR gene. The effect of low-T on vitality was observed only when the genetically-determined sensitivity of the androgen receptor is at its greatest. Variations in the AR gene, bestowing differential androgen sensitivity, are potential targets for personalized therapy of hypogonadism. Future studies are needed to determine how genetic information can be used to improve the efficacy of TRT © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1223 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Matthew Panizzon More articles by this author Tung-Chin Hsieh More articles by this author Franz Carol More articles by this author Richard Hauger More articles by this author William Kremen More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Androgen receptor gene CAG repeat polymorphism and ovarian cancer risk: A meta-analysis.

Ovarian cancer is one of the common gynecological malignancies worldwide. It is usually diagnosed at a later stage, thus missing the best opportunity for treatment. Despite the advancement of ovarian cancer treatment, the prognosis is still poor. Androgen receptor (AR) may play a role in ovarian carcinogenesis. Previous studies regarding the association between AR CAG repeat length and ovarian cancer risk reported inconsistent results. Therefore, we conducted a meta-analysis to evaluate the association between AR CAG repeat length and ovarian cancer risk following the MOOSE guidelines. PubMed, Web of Science, EBSCO and other databases were searched up to September 15th 2016. Case control studies with clear definition of CAG repeat length and detailed genotype information were included. Two authors independently reviewed and extracted data. Pooled analysis and subgroup analysis stratified by ethnicity were performed for different genetic models. Begg's funnel plot and Egger's test were performed for publication bias estimation. Overall, there was no association between the AR CAG repeat polymorphism and ovarian cancer risk. However, short CAG repeat polymorphism was associated with increased ovarian cancer risk in African Americans and Chinese under the dominant model, whereas a reverse association was observed in Caucasians and Italians under the other three models. Our study results should be interpreted with caution. Further well-designed epidemiological and functional studies are needed to elucidate the role of AR in ovarian carcinogenesis.

Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment.

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor (AR). Sperm production may be affected in men treated for testicular cancer (TC), and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients (n = 130) delivered ejaculates at the following time points: postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy (T0, T6, T12, T24, T36, and T60). The CAG lengths were categorized into three groups, <22 CAG, 22–23 CAG, and >23 CAG, and the GGN tracts were also categorized into three groups, <23 GGN, 23 GGN, and >23 GGN. At T12, men with 22–23 CAG presented with a statistically significantly (P = 0.045) lower sperm concentration than those with other CAG numbers (8.4 × 106 ml−1 vs 16 × 106 ml−1; 95% CI: 1.01–2.65). This association was robust to omitting adjustment for treatment type and sperm concentration at T0 (P = 0.021; 3.7 × 106 ml−1 vs 10 × 106 ml−1; 95% CI: 1.13–4.90). The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men.

The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. Multinational European observational prospective cohort study. A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis. Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Genetic Association Between Androgen Receptor Gene CAG Repeat Length Polymorphism and Male Infertility: A Meta-Analysis.

The association between polymorphism of androgen receptor gene CAG (AR-CAG) and male infertility in several studies was controversial. Based on studies on association between AR-CAG repeat length and male infertility in recent years, an updated meta-analysis is needed. We aimed to evaluate the association between AR-CAG repeat length and male infertility in advantage of the data in all published reports.We searched for reports published before August 2015 using PubMed, CNKI, VIP, and WanFang. Data on sample size, mean, and standard deviation (SD) of AR-CAG repeat length were extracted independently by 3 investigators.Forty-four reports were selected based on criteria. The overall infertile patients and azoospermic patients were found to have longer AR-CAG repeat length (standard mean difference (SMD) = 0.19, 95% confidence interval (CI): 0.10-0.28, P < 0.01; SMD = 0.36, 95% CI: 0.10-0.61, P < 0.01). AR-CAG repeat length was longer in infertile men in Asian, Caucasian, and mixed races (SMD = 0.25, 95% CI: 0.08-0.43, P <0.01; SMD = 0.13, 95% CI: 0.02-0.25, P <0.05; SMD = 0.39, 95% CI: 0.15-0.63, P <0.01). The overall study shows that increased AR-CAG repeat length was associated with male infertility. The subgroup study on races shows that increased AR-CAG repeat length was associated with male infertility in Asian, Caucasian, and mixed races. Increased AR-CAG repeat length was also associated with azoospermia.This meta-analysis supports that increased androgen receptor CAG length is capable of causing male infertility susceptibility.

The interaction of serum testosterone levels and androgen receptor CAG repeat polymorphism on the risk of erectile dysfunction in aging Taiwanese men.

Testosterone has been found to play important roles in men's sexual function. However, the effects of testosterone can be modulated by androgen receptor (AR) CAG repeat polymorphism. It could also contribute to the risk of erectile dysfunction (ED). The aim of this study is to evaluate the interaction of serum testosterone levels and AR CAG repeat polymorphism on the risk of ED in aging Taiwanese men. This cross-sectional data of Taiwanese men older than 40 years were collected from a free health screening held between August 2010 and August 2011 in Kaohsiung city, Taiwan. All participants completed a health questionnaires included five-item version of the International Index of Erectile Function (IIEF-5) and the International Prostate Symptoms Score, received a detailed physical examination and provided 20 cm3 whole blood samples for biochemical and genetic evaluation. The IIEF-5 was used to evaluate ED. Serum albumin, total testosterone (TT), and sex hormone-binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. Finally, 478 men with the mean age of 55.7 ± 4.8 years were included. When TT levels were above 330 ng/dL, the effect of testosterone level on erectile function seemed to reach a plateau and a significantly negative correlation between AR CAG repeat length and the score of IIEF-5 was found (r = -0.119, p = 0.034). After adjusting for other covariates, the longer AR CAG repeat length was still an independent risk factor for ED in subjects with TT above 330 ng/dL (p = 0.006), but not in TT of 330 ng/dL or below. In conclusion, both serum testosterone levels and AR CAG repeat polymorphism can influence erectile function concomitantly. In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing ED.

Relationship between gene polymorphisms and prostate cancer risk.

To investigate the relationship between genetic factor and prostate cancer (Pca) risk and the possible cause in it. The polymorphisms of cytochrome P450 family 17 (CYPl7) rs743572, p27 V109G and androgen receptor (AR) gene CAG repeat length in peripheral blood from 70 cases and 70 controls were detected through the polymerase chain reaction-restriction fragment length polymorphism technique or short tandem repeat-polymerase chain reaction technique. Then, according to the results of case-control study, the recombinant plasmids containing the wild/mutant p27 gene were constructed and transfected Pca LNcap cells. After 24 and 72h of transfection, the cell proliferative activity was determined by MTT method, cell cycle distribution and apoptosis was detected by flow cytometry, and the expression level of bcl-2, caspase-3 and p27 protein was determined by Western-blot. In three target polymorphisms, only p27 V109G polymorphism was related to Pca risk (P=0.030, OR=0.202, 95% CI=0.042-0.973). Pca risk of p27-109G allele was lower than-109V allele (P=0.006, OR=0.285, 95% CI=0.110-0.737). Cells transfected with wild/mutant p27 gene both showed the higher cells apoptosis rate and the lower cell proliferative activity than mock cells (P<0.05 or 0.01), the regulatory effect of mutant p27 on cell proliferation and apoptosis was stronger than the wild p27 (P<0.05). p27-109G allele that could cause higher p27 protein expression than-109V allele in LNcap cells, maybe is the protective factor of Pca.

Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis.

Studies investigating the association between the CAG repeat polymorphism and the risk of isolated hypospadias have reported conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, Embase, CNKI, and Wanfang databases. Weighted mean difference and 95% confidence intervals for the CAG repeat polymorphism and isolated hypospadias were calculated using a random-effects model. Subgroup analyses were performed by race, study design, sample for DNA extraction, and hypospadias classifications. This meta-analysis included 6 case-control studies, including 444 isolated hypospadias cases and 727 controls. The results showed that patients with isolated hypospadias had longer CAG repeats in their androgen receptor gene sequence (weighted mean difference = 1.36, 95% confidence interval = 0.60-2.13; P = 0.0005). Similarly, stratified analyses also detected significant associations in all subgroups, excluding the group with severe hypospadias (weighted mean difference = 0.35, 95% confidence interval = -0.42-1.12; P = 0.38). This meta-analysis indicated that longer CAG repeats were associated with the risk of isolated hypospadias, and that longer CAG polymorphisms may be related to the etiology of isolated hypospadias. Future studies based on Asian and African-American patients should be performed to re-evaluate this association.