Androgen Receptor CAG Repeat Length Research Articles

FRI431 Erythrocytosis Associated With Oral Testosterone Replacement

Abstract Disclosure: A.A. Engel: None. J.L. Sarvaideo: None. Background: A growing prevalence in male hypogonadism has led to increased interest in the most common adverse event, erythrocytosis. Defined by hematocrit (HCT) > 49-51%, the incidence varies depending on the testosterone formulation.3 The formulations with the lowest risk of erythrocytosis are intranasal testosterone (0-2%) and oral testosterone (0.03%).3 A phase 3 clinical trial of testosterone undecanoate (Jatenzo) reported 4.8% patients experienced an increase in hematocrit, although not severe enough to warrant therapy discontinuation.2 We present a case of erythrocytosis with oral testosterone undecanoate that prompted a change in therapy. Clinical Case: Our patient is a 55-year-old male with secondary hypogonadism potentially related to obesity (BMI 37 kg/m²). AM total testosterone (TT) 151 (348-1197 ng/dL), free testosterone 4.6 pg/mL (6.8-21.5 pg/mL) and LH 3.8 mIU/mL. Labs confirmed. Secondary work-up negative. HCT 43.6% prior to any therapy. Patient treated with injectable testosterone. Despite decreasing to testosterone cypionate 80 mg weekly his HCT increased to 52.7% with a TT of 544 ng/dL. He was switched to oral testosterone undecanoate 237 mg twice daily given presumably lower risk of erythrocytosis. However, HCT increased to 55.1% and TT to 1542 ng/dL. Patient donated blood and oral testosterone dose decreased to 158 mg twice daily with starting HCT 48.9%, but this increased to 53.7%. TT 522 ng/dL. Therapy stopped with improvement of HCT to 45.8%-48.9%, TT 192 ng/dL, and SHBG 20 g/dL. Erythropoietin remained normal. Patient does not smoke cigarettes nor has OSA. Conclusion: We present a case of oral testosterone undecanoate complicated by persistent erythrocytosis despite dose reduction. Testing for contributing etiology was unrevealing. Oral testosterone replacement is considered the formulation least likely to cause erythrocytosis. Certain patient characteristics like OSA, advanced age, obesity, type II diabetes mellitus and an elevated HCT > 50% can predict the likelihood of erythrocytosis although its specific etiology is unclear.3 Proposed mechanisms include elevation in dihydrotestosterone, erythropoietin stimulation, suppression of hepcidin and relation to androgen receptor CAG repeat length.1 Providers should be aware of the possibility of erythrocytosis on oral testosterone. Further research is needed to determine predictive characteristics for erythrocytosis and etiology. Reference: 1. Aghazadeh, M, et al. Elevated dihydrotestosterone is associated with testosterone induced erythrocytosis. J Urol. 2015; 194(1): 160-165. 2. Swerdloff, S, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020; 105)8): 1-17. 3. White, J, et al. Testosterone therapy and secondary erythrocytosis. IJIR: Your Sexual Medicine Journal. 2022; 34: 693-697. Presentation: Friday, June 16, 2023

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.

Reproductive hormone levels, androgen receptor CAG repeat length and their longitudinal relationships with decline in cognitive subdomains in men: The European Male Ageing Study.

ObjectiveIt has been proposed that endogenous sex hormone levels may present a modifiable risk factor for cognitive decline. However, the evidence for effects of sex steroids on cognitive ageing is conflicting. We therefore investigated associations between endogenous hormone levels, androgen receptor CAG repeat length, and cognitive domains including visuoconstructional abilities, visual memory, and processing speed in a large-scale longitudinal study of middle-aged and older men. MethodsMen aged 40-79 years from the European Male Ageing Study (EMAS) underwent cognitive assessments and measurements of hormone levels at baseline and follow-up (mean = 4.4 years, SD ± 0.3 years). Hormone levels measured included total and calculated free testosterone and estradiol, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulphate and sex hormone-binding globulin. Cognitive function was assessed using the Rey-Osterrieth Complex Figure Copy and Recall, the Camden Topographical Recognition Memory and the Digit Symbol Substitution Test. Multivariate linear regressions were used to examine associations between baseline and change hormone levels, androgen receptor CAG repeat length, and cognitive decline. ResultsStatistical analyses included 1,827 and 1,423 participants for models investigating relationships of cognition with hormone levels and CAG repeat length, respectively. In age-adjusted models, we found a significant association of higher baseline free testosterone (β=-0.001, p=0.005) and dihydrotestosterone levels (β=-0.065, p=0.003) with greater decline on Rey-Osterrieth Complex Figure Recall over time. However, these effects were no longer significant following adjustment for centre, health, and lifestyle factors. No relationships were observed between any other baseline hormone levels, change in hormone levels, or androgen receptor CAG repeat length with cognitive decline in the measured domains. ConclusionsIn this large-scale prospective study there was no evidence for an association between endogenous sex hormone levels or CAG repeat length and cognitive ageing in men. These data suggest that sex steroid levels do not affect visuospatial function, visual memory, or processing speed in middle-aged and older men.

Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men.

Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs normal testosterone values and some androgen deficiency linked pathologies. Blood samples from 30 healthy GnRH antagonist treated males were collected at three time points: (1) before GnRH antagonist administration; (2) 3 weeks later, just before testosterone undecanoate injection, and (3) after additional 2 weeks. Subsequently, they were analyzed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardiometabolic parameters, bone mineral density as well as androgen receptor (AR) CAG repeat lengths, were explored. Using receiver operating characteristic analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6), and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (<8 nmol/l) vs normal (>12 nmol/l) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD also showed association with AR CAG repeat lengths. We identified potential new protein biomarkers of testosterone action. Further investigations to elucidate their clinical potential are warranted. The work was supported by ReproUnion2.0 (grant no. 20201846), which is funded by the Interreg V EU program.

Polymorphisms of androgens-related genes and idiopathic male infertility in Turkish men.

Androgens, testosterone and dihydrotestosterone (DHT) are endocrine regulators of spermatogenesis and act via androgen receptor (AR). The aim of this study was to investigate the association(s) of AR (CAG repeat length), SRD5A2 (rs523349, V89L) and TNF-α (rs1800629, -308G/A) polymorphisms with idiopathic male infertility in Turkish men. This case-control study consisted of 312 men with idiopathic infertility and 113 fertile men. Polyacrylamide gel electrophoresis (PAGE) or PCR-restriction fragment length polymorphism methods were used for genotyping. The mean AR CAG repeat length was significantly longer in infertile men than in fertile men (p=0.015). However, there was no significant association between the SRD5A2 genotypes (VV, VL and LL) and the risk of infertility (p=0.516). The genotype frequency and allele distribution of TNF-α -308G/A polymorphism (GG, GA, AA genotypes and G, A alleles) were not associated with male infertility (p=0.779 and p=0.743 respectively). AR CAG repeat expansion might be one of the risk factors for idiopathic male infertility in Turkish men. Further studies investigating the association of male infertility with AR CAG, V89L and -308G/A polymorphisms are warranted to understand the possible associations among them.

Cognitive impairment and associations with structural brain networks, endocrine status, and risk genotypes in newly orchiectomized testicular cancer patients

A higher incidence of cognitive impairment (CI) has previously been reported among orchiectomized testicular cancer patients (TCPs), but little is known about the underlying pathophysiology. The present study assessed CI in newly orchiectomized TCPs and explored the structural brain networks, endocrine status, and selected genotypes. Forty TCPs and 22 healthy controls (HCs) underwent neuropsychological testing and magnetic resonance imaging, and provided a blood sample. CI was defined as a z-score ≤ -2 on one neuropsychological test or ≤ -1.5 on two neuropsychological tests, and structural brain networks were investigated using graph theory. Associations of cognitive performance with brain networks, endocrine status (including testosterone levels and androgen receptor CAG repeat length), and genotypes (APOE, BDNF, COMT) were explored. Compared with HCs, TCPs performed poorer on 6 out of 15 neuropsychological tests, of which three tests remained statistically significant when adjusted for relevant between-group differences (p< 0.05). TCPs also demonstrated more CI than HCs (65% vs. 36%;p = 0.04). While global brain network analysis revealed no between-group differences, regional analysis indicated differences in node degree and betweenness centrality in several regions (p < 0.05), which was inconsistently associated with cognitive performance. In TCPs, CAG repeat length was positively correlated with delayed memory performance (r = 0.36;p = 0.02). A COMT group × genotype interaction effect was found for overall cognitive performance in TCPs, with risk carriers performing worse (p = 0.01). No effects were found for APOE, BDNF, or testosterone levels. In conclusion, our results support previous findings of a high incidence of CI in newly orchiectomized TCPs and provide novel insights into possible mechanisms.

Androgen receptor polymorphism, mental rotation, and spatial visualization in men

Circulating levels of testosterone (T) have been hypothesized to influence spatial cognition in adult men, but empirical support for this idea is mixed. Many of testosterone’s effects are mediated by the classic nuclear androgen receptor (AR), which contains a polymorphic glutamine repeat (CAG repeat sequence) that varies significantly across individual men and confers differences in receptor function and therefore individual responsivity to T. We genotyped the AR CAG repeat length in 146 healthy adult men who also performed cognitive tests of mental rotation and spatial visualization. Circulating T concentrations were measured in saliva. CAG repeat length was found to be a significant predictor of spatial scores on tests of visualization but not mental rotation. A weaker AR was associated with lower visualization scores. In contrast, T itself, but not CAG repeat length predicted scores on two mental rotation tests. These results support the view that T action in the brain modestly influences spatial cognition in healthy men, but suggest that T’s effects on mental rotation might not be AR-dependent and instead occur through an alternative mechanism.

Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.

Abstract 3507: Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer

Abstract Prostate cancer (PCa) is the second most common cancer diagnosed in men globally, after lung cancer. PCa incidence, aggressiveness and mortality are significantly higher among African Americans (AAs) compared with men of other racial/ethnic groups. Despite the worse prognosis associated with African ancestry, several recent studies have shown that PCa patients of African ancestry have a better response to certain PCa therapeutic regimens than those of European ancestry. The overall objective of our study is to identify ancestry-related genetic variation that associates with outcomes on abiraterone/prednisone therapy in metastatic castration-resistant prostate cancer (mCRPC). Our central hypothesis is that differences in ancestry-related single nucleotide polymorphisms (SNPs), gene expression and polymorphic CAG trinucleotide repeats located in the androgen receptor (AR) gene will associate with prostate-specific antigen (PSA) response and time to progression on secondary hormonal therapy in mCRPC patients. Toward our objective, we collected whole blood at baseline and archival tumor tissue from 50 self-identified AA and 50 self-identified white patients enrolled in the Abi Race study, a Phase II study of abiraterone/prednisone in AA and white men with mCRPC. To perform ancestral and genome-wide genotyping, we isolated DNA from the whole blood samples collected at baseline and interrogated DNA using the Infinium Multi-Ethnic Global BeadChip (Illumina). We identified nine candidate SNPs in genes having previously reported relevance to cancer and/or PCa that were associated with longer time to confirmed PSA progression (TTP) in blacks and shorter TTP in whites. To perform gene expression profiling, we isolated RNA from archival formalin-fixed, paraffin-embedded PCa tissue and interrogated RNA using a NanoString Custom CodeSet (NanoString Technologies). Preliminary analysis revealed significant race-related differential expression of 30 PCa-related genes. To accomplish AR CAG repeat length profiling, we performed PCR using primers flanking the CAG repeat region and utilized a DNA Bioanalyzer to measure the relative nucleotide length. AR CAG repeat lengths varied from 8 to 40 and we are currently investigating the association between length and patient outcomes on abiraterone/prednisone therapy. Future analyses will focus on defining the functional significance of the aforementioned ancestry-related genetic variation using preclinical cancer models and validation of the aforementioned ancestry-related genetic variation in an independent cohort. These findings will further understanding of ancestry-related biological factors that influence response to secondary hormonal therapy in mCRPC and could have direct implications for the timing and selection of AA patients for secondary hormonal therapy and those needing additional therapy. As secondary hormonal therapy use expands to earlier disease settings, these findings could support the need for further studies in AA men in these disease settings. Ultimately, such strategies have the potential to mitigate PCa disparity. Citation Format: Tyler Allen, Gary Lipton, Alexander B. Sibley, Patrick Healy, Brendon Patierno, Bonnie Lacroix, Steven Patierno, Kouros Owzar, Terry Hyslop, Daniel J. George, Jennifer A. Freedman. Race-related genetic variation and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3507.

Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

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.

Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population.

BackgroundTestosterone action is mediated through the androgen receptor (AR), whose sensitivity is influenced by the AR CAG repeat polymorphism. However, the relation between late-onset hypogonadism (LOH) and AR CAG repeat length is unclear and studies of Asian populations are limited.AimTo investigate the relation between AR CAG repeat length and LOH in Korean men.Methods263 Korean men (mean age = 63.43 ± 10.9 years) were enrolled from 2014 to 2015. LOH diagnosis was based on a serum testosterone level lower than 3.5 ng/mL and positive androgen deficiency according to the Aging Males’ Symptom Scale (AMS). Total testosterone levels and answers to the LOH-related questionnaire were analyzed.OutcomesThe relation between AR CAG repeat length and LOH was determined.ResultsMean CAG repeat length was 22.1 ± 4.6 and mean serum testosterone levels were 2.6 ± 0.7 and 6.0 ± 2.0 ng/mL in men with and without LOH, respectively. Men with LOH showed significantly longer AR CAG repeat lengths than men without LOH (26.1 vs 21.6, P < .001). Longer CAG repeat lengths were correlated with higher AMS total scores (r = 0.454, P = .001) and AMS psychotic, somatic, and sexual sub-scores (r = 0.276, 0.246, and 0.571, P = .006, .007, .001, respectively) and significantly lower 5-item International Index of Erectile Function scores (r = −0.261, P = .001). Multivariate analysis showed that patient age and CAG repeat length were independently associated with LOH (odds ratio = 1.05 and 1.29, P = .041 and <.001, respectively).Clinical ImplicationsA longer CAG repeat length is associated with LOH symptoms and LOH.Strengths and LimitationsAssociations between CAG repeats and LOH were verified in Korean patients. Moreover, a longer CAG repeat length was shown to be an independent risk factor for LOH. Limitations included the small number of LOH patients studied and that other sex hormone-associated factors were not measured.ConclusionsAR CAG repeat length was associated with LOH prevalence and clinical symptoms in this Korean male population. Thus, it is important to measure CAG repeat length for patients with LOH symptoms with normal testosterone levels.Kim JW, Bae YD, Ahn ST, et al. Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population. Sex Med 2018;6:203–209.

Positive Correlation between Androgen Receptor CAG Repeat Length and Metabolic Syndrome in a Korean Male Population

PurposeIn epidemiological studies, there are various associations of androgen receptor (AR) CAG with several diseases or phenotypes. However, the relationship between CAG repeat length and metabolic syndrome (MS) remains unclear, especially in Asian populations. This study was designed to evaluate the relationship between AR CAG repeat length polymorphism and MS in a Korean male population.Materials and MethodsWe explored the relationship between AR CAG repeat length polymorphism and MS in a Korean male population (n=337) from 2013 to 2014. AR CAG repeat were determined by microsatellite fragment sizing. Components of MS and laboratory data (lipid profile, fasting glucose, and glycated hemoglobin (HbA1c)) were analyzed with AR CAG repeat length.ResultsThe mean AR CAG repeat length was 22.3±4.7. Sixty-nine men (20.5%) were diagnosed with MS. Men with MS showed significantly longer AR CAG repeat lengths compared with men without MS (26.2 vs. 21.4, p<0.001). With increasing CAG repeat, the number of components meeting the NCEP criteria increased significantly. AR CAG repeat length was associated significantly with high density lipoprotein (HDL), triglyceride, and HbA1c levels. In the multivariate analysis, CAG repeat length, waist circumference, and levels of HDL were independently associated with MS. (odds ratio (OR)=1.37, 1.19 and 0.90, p<0.001, 0.045, and 0.001, respectively).ConclusionsAR CAG repeat length was associated with MS and laboratory test results, such as those for HDL, triglycerides, and HbA1c, in Korean males. Longer CAG repeat length was identified as a risk factor for MS in Korean males.

Androgen receptor cytosine, adenine, and guanine trinucleotide repeat polymorphism in Korean patients with endometriosis: A case-control study

Study objective: To investigate the association between the androgen receptor (AR) cytosine, adenine, and guanine (CAG) repeat polymorphisms and endometriosis. Study design: A prospective case-control, genetic association study was performed on women with surgically proven endometriosis (n=421) and controls free of endometriosis (n=349). AR CAG repeat lengths were determined from peripheral blood samples. The difference in the frequency of each alleles were compared in patients with endometriosis and controls using Chi-square test. Main results: No significant difference in biallelic length mean between patients and controls was observed. Alleles containing 24 CAG repeats were significantly more frequent in stage I–II (mild) endometriosis than in the control samples (19.8% and 13.3%, respectively; OR 1.60, 95% CI 1.04-2.47). Additionally, a higher frequency of both alleles with 24 or more CAG repeats was observed in individuals with mild endometriosis, in comparison with the controls (25.6% and 15.2%, respectively; OR 1.92, 95% CI 1.09-3.38). ConclusionsAR gene CAG repeat polymorphisms are associated with the increased risk of mild endometriosis.

AB018. Androgen receptor CAG repeat length polymorphism as a risk factor of late onset hypogonadism/metabolic syndrome in a Korean male population

BackgroundAndrogen receptor (AR) CAG polymorphism modulates the effect of testosterone in target organs. However, correlation between AR CAG repeat length and clinical features of late onset hypogonadism (LOH) is unclear and there are only few studies from Asian population. In this study, we explored the relationship of AR CAG repeat length polymorphism with LOH and metabolic syndrome (MS) in Korean male population.MethodsThe association between AR CAG repeat length and LOH, MS were studied in a total of 600 Korean men from 2013 to 2015. LOH was diagnosed by serum testosterone level of <3.5 ng/mL and ADAM questionnaire. AR CAG repeat length was determined by microsatellite fragment sizing. MS was diagnosed with NCEP criteria ATP III. Clinical factors and questionnaire related with LOH [patient health questionnaire-9 (PHQ), aging male symptom scale (AMS), and international index of erectile function (IIEF-5)] were analyzed with AR CAG repeat length.ResultsMean age of the patients was 61.2±10.9 years and mean AR CAG repeat length was 22.2±5.1. Mean serum testosterone levels was 2.6±0.7 in men with LOH and 6.0±2.0 in men without LOH, respectively. A total of 33 men (12.5%) were diagnosed with LOH. Men with LOH showed significant longer AR CAG repeat length compared with men without LOH (26.1 vs. 21.6, P<0.001). As CAG repeat length increased, AMS total and AMS psychotic/somatic/sexual subscore increased (r=0.219, r=0.168, r=0.160, r=0.241) (P=0.001, P=0.006, P=0.001, P=0.001) and IIEF-5 score decreased, significantly (r=−0.187, P=0.002). In multivariate analysis showed that CAG and total AMS score were independently associated with LOH. (OR =1.3, 0.9, P<0.001, 0.005, respectively) Men with MS showed significant longer AR CAG repeat length compared with men without MS (26.2 vs. 21.4, P<0.001). As CAG repeat length increased, number of components of NCEP criteria increased, significantly (R2 =0.119, P=0.001). AR CAG repeat length showed significant correlation with HDL (r=−0.244, P<0.001), triglyceride (r=0.276, P<0.001), HbA1c (r=0.201, P<0.001). In multivariate analysis, CAG repeat length, waist circumference and HDL were independent risk factors of MS.ConclusionsIn conclusion, AR CAG repeat length was associated with prevalence of LOH and clinical symptoms of LOH in a Korean male population. Longer CAG repeat length was identified as one of the risk factor of LOH and MS in Korean male.

Retraction: Androgen receptor CAG and GGN repeat length variation contributes more to the tumorigenesis of osteosarcoma.

// Yongxiang Shi 1 , Weishan Chen 1 , Qinghuai Li 2 , Zhaoming Ye 1 1 Department of Orthopaedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Department of Medicine, 3rd Hospital of Henan Province, Henan, China Correspondence to: Zhaoming Ye, email: ye_zhaoming@163.com Keywords: osteosarcoma, papillary thyroid cancer, AR, repeat, CAG Received: May 24, 2016 Accepted: August 13, 2016 Published: September 08, 2016 ABSTRACT The androgen receptor ( AR ) is involved in the differentiation and growth of many cancers. We hypothesized that two microsatellite polymorphic variants, AR (CAG)n and (GGN)n repeats, were also associated with the development of Papillary thyroid cancer (PTC) and Osteosarcoma. In current study, we conducted two case-control studies in a Chinese population to investigate the possible relationship between these two AR repeat polymorphisms and the risk of PTC and Osteosarcoma. The AR CAG repeat length was significantly associated with both risk of PTC and Osteosarcoma. Subjects with shorter AR CAG repeats had a higher risk of developing PTC (OR = 1.47, 95% CI: 1.17–1.85, P = 0.001) and Osteosarcoma (OR = 1.53, 95% CI: 1.19–1.97, P = 9.2 x 10 –4 ). Specifically, shorter GGN repeats also contribute a significant increased risk of Osteosarcoma (OR = 1.35, 95% CI: 1.03–1.77, P = 0.030). Our results contribute to a better understanding of the complex hormone related mechanisms underlying PTC and Osteosarcoma.

MP81-19 ANDROGEN RECEPTOR CAG REPEAT LENGTH AS A RISK FACTOR OF LATE ONSET HYPOGONADISM IN A KOREAN MALE POPULATION

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology II1 Apr 2017MP81-19 ANDROGEN RECEPTOR CAG REPEAT LENGTH AS A RISK FACTOR OF LATE ONSET HYPOGONADISM IN A KOREAN MALE POPULATION Sun Tae Ahn, Hyeong Guk Jeong, Ji Yun Chae, Jong Wook Kim, Mi Mi Oh, Hong Seok Park, Je jong Kim, and Du Geon Moon Sun Tae AhnSun Tae Ahn More articles by this author , Hyeong Guk JeongHyeong Guk Jeong More articles by this author , Ji Yun ChaeJi Yun Chae More articles by this author , Jong Wook KimJong Wook Kim More articles by this author , Mi Mi OhMi Mi Oh More articles by this author , Hong Seok ParkHong Seok Park More articles by this author , Je jong KimJe jong Kim More articles by this author , and Du Geon MoonDu Geon Moon More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2545AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen receptor (AR) CAG polymorphism that modulates the effect of testosterone has been found to influence sexual function. However, correlation between AR CAG repeat length and clinical factors of late onset hypogonadism is unclear and there are only few studies from Asian population. In this study we explored the relationship between AR CAG repeat length polymorphism and late onset hypogonadism (LOH) in a Korean male population. METHODS The association between AR CAG repeat length was analyzed in a total 263 Korean men from 2014 to 2015. LOH was diagnosed by serum testosterone level of <3.5ng/mL and androgen deficiency in the aging male questionnaire positive. AR CAG repeat length was determined by microsatellite fragment sizing. Clinical factors and questionnaire related with LOH (patient health questionnaire-9 (PHQ), aging male symptom scale (AMS), and international index of erectile function (IIEF-5)) were analyzed with AR CAG repeat length. RESULTS Mean age of the patients was 61.2±10.9 years and mean AR CAG repeat length was 26.2±5.1. Mean serum testosterone levels was 2.6±0.4 in men with LOH and 6.0±2.0 in men without LOH, respectively. A Total of 33 men (12.5%) were diagnosed with LOH. Men with LOH showed significant longer AR CAG repeat length compared with men without LOH (30.1 vs 25.6, p<0.001). As CAG repeat length increased, AMS total and AMS psychotic/somatic/sexual subscore increased(r=0.219 r=0.168, r=0.160, r=0.241) (p=0.001,p=0.006 p=0.001, p=0.001) and IIEF-5 score decreased, significantly (r=-0.187 p=0.002). In multivariate analysis showed that CAG was independently associated with LOH. (OR=1.3, P<0.001) CONCLUSIONS AR CAG repeat length was associated with prevalence of LOH and clinical symptoms of LOH in a Korean male population. Longer CAG repeat length was identified as a risk factor of LOH in Korean male. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1096 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Sun Tae Ahn More articles by this author Hyeong Guk Jeong More articles by this author Ji Yun Chae More articles by this author Jong Wook Kim More articles by this author Mi Mi Oh More articles by this author Hong Seok Park More articles by this author Je jong Kim More articles by this author Du Geon Moon More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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 ...

131 Correlation between androgen receptor CAG repeat length polymorphism and metabolic syndrome, late onset hypogonadism in Korean male

131 Correlation between androgen receptor CAG repeat length polymorphism and metabolic syndrome, late onset hypogonadism in Korean male

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.