Androgen Receptor CAG Repeat Polymorphism Research Articles

Associations of CAG repeat polymorphism in the androgen receptor gene with steroid hormone levels and anthropometrics among men: the role of the ethnic factor.

Androgens are required for stimulation and maintenance of skeletal growth and bone homeostasis. Physiological functions of androgens are mediated through the androgen receptor (AR). The androgen receptor gene AR has a polymorphic trinucleotide CAG repeat and the length of AR CAG repeats determining the sensitivity of bone tissue to androgens is associated with skeleton formation and body proportions. This study aimed to investigate the relationship between AR CAG repeat polymorphism, circulating sex steroid hormones and the anthropometrics in males of different ethnic origins. Male volunteers of three ethnic groups (Slavs, Buryats, Yakuts) from urban Russian populations were recruited in a population-based study (n = 1078). Anthropometric indicators (height, arm span, leg length, the length of 2 and 4 digits of both hands) were measured and the following anthropometric indices were calculated: the ratio of height to leg length, the ratio of arm span to height, the ratio of lengths of second to fourth digit of the hand. Serum testosterone and estradiol were determined by enzyme immunoassay. Genotyping of the AR CAG repeats was performed using fragment analysis and capillary electrophoresis. Ethnic differences in all anthropometric and hormonal indicators have been established, with higher anthropometric indicators in Slavs than Buryats, and in most cases higher than in Yakuts. The testosterone level was higher among Slavs compared to Buryats, but did not differ from Yakuts; the estradiol level was lower among Slavs compared to Buryats, who did not differ from Yakuts. Buryats and Yakuts had a higher number of CAG repeats than Slavs (medians: Slavs, 23; Buryats, 24; Yakuts, 25). Positive correlations were found between the length of AR CAG repeats and estradiol levels in Buryats and testosterone levels in Yakuts, while longer CAG repeats were accompanied by higher estradiol levels in Buryats and testosterone levels in Slavs and Yakuts. Ethnic-specific correlations have been established between the steroid hormone levels and some anthropometric indicators in all ethnic groups. Available data suggest that the ethnic-specific associations of AR CAG repeats with anthropometrics can be mediated by sex steroid hormones as important regulators of skeletal growth and bone homeostasis.

Investigation of the role of X chromosome inactivation and androgen receptor CAG repeat polymorphisms in patients with recurrent pregnancy loss: a prospective case–control study

BackgroundPrevious research has revealed that skewed X chromosome inactivation (SXCI) and androgen receptor (AR) CAG polymorphisms are associated with increased risk of recurrent pregnancy loss (RPL); however, the results are conflicting, and the underlying mechanisms remain unclear. This study investigated the role of SXCI and AR CAG polymorphisms in patients with RPL and explored whether the underlying mechanisms were related to the ovarian reserve and preimplantation embryo aneuploidy.MethodsThis was a prospective case-control study carried out in a tertiary hospital-based reproductive medicine center. An external validation RPL cohort was recruited during the study period. Data on baseline and cycle characteristics were collected. X-chromosome inactivation (XCI) was measured using a human AR assay. AR polymorphisms were assessed using quantitative fluorescent polymerase chain reactions and direct sequencing. Blastocysts of the patients with RPL were tested by single nucleotide polymorphism microarray based preimplantation genetic testing for aneuploidy.ResultsIn total, 131 patients with idiopathic RPL and 126 controls were included for the case-control study. Patients with RPL exhibited a significantly more skewed XCI distribution pattern (67.71 ± 10.50 vs. 64.22 ± 10.62, p = 0.011), as well as significantly shorter bi-allelic mean (18.56 ± 1.97 vs. 19.34 ± 2.38, p = 0.005) and X-weighted bi-allelic mean (18.46 ± 2.02 vs. 19.38 ± 2.53, p = 0.001) of AR CAG repeats. Multivariate logistic regression models indicated that CAG repeat < 20, SXCI, and duration of stimulation were independently associated with the risk of RPL. However, SXCI and AR CAG polymorphisms were not associated with ovarian reserve or preimplantation embryo aneuploidy in the RPL group, and the same results were attained in a separate validation cohort of 363 patients with RPL.ConclusionSXCI and AR CAG polymorphisms are related to RPL; however, these two factors do not lead to RPL by affecting the ovarian reserve or increasing embryo aneuploidy. The roles of SXCI and AR CAG in RPL may involve other mechanisms that require further investigation.Trial registration:NCT02504281, https://www.clinicaltrials.gov (Date of registration, 21/07/2015; date of enrolment of the first subject, 30/07/2015).

The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism.

The study aimed to investigate whether repeat number in the androgen receptor (AR) gene has any contribution to phenotypes of the disease of androgen excess (polycystic ovary syndrome (PCOS), idiopathic hyperandrogenemia (IHA) and idiopathic hirsutism (IH) in a cohort of Turkish women. Three hundred and fifty-four voluntary premenopausal women (172 healthy controls and 182 patients with androgen excess disorders and idiopathic hirsutism) 18-45years of age seen at an outpatient endocrine clinic at Erciyes University Hospital between January 2013 and December 2014 were included. All volunteers have undergone physical examination and biochemical evaluation. The polymorphic (CAG)n repeat of the human AR was determined by fragment analyses. Detailed clinical analyses of the patients ended up with 137 PCOS, 24 IHA, and 21 IH. Pairwise comparisons revealed the CAG repeat number differences between the PCOS and controls (p = 0.005) and IH and controls (p = 0.020). Women with CAG repeat length ≤ 17 had a significantly increased twofold risk for PCOS than those women with > 17 CAG repeats OR: 2.0 (95% CI 1.2-3.3, p = 0.005). Women with CAG repeat length ≤ 17 had a significantly increased threefold risk for IH than those women with > 17 CAG repeats OR: 2.9 (95% CI 1.2-7.3, p = 0.020). When correlation analysis was performed, a weak negative correlation was detected between the short allele and FGS score (r = - 0.131, p = 0.013) and a positive relationship between total testosterone and longer allele in the IHA group (r = 0.425, p = 0.039). Median repeat length of the shorter allele between oligomenorrhea and woman with normal menstrual cycle was found to be statistically significant (p = 0.017). This study indicated that the risk of PCOS and IH is associated with the inheritance of ARs with shorter 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.

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.

The polymorphic CAG repeat in exon 1 of androgen receptor is associated with level of HDL cholesterol and hypertension in Chinese middle-aged and elderly men.

The length of the CAG repeats in exon 1 of the androgen receptor (AR) gene has been shown to be inversely correlated with AR transcriptional activity. This study aimed to investigate the correlations between the length of CAG repeat in AR and serum lipids and hypertension in Chinese men. The relationship between length of the CAG repeat in exon 1 of AR with prevalence of hypertension and the levels of serum lipids among Chinese men (aged ≥40years). The physical condition of the subjects was examined and recorded. The concentrations of blood lipids and sex hormones were measured, and the CAG repeat lengths of the AR gene were determined. The length of the AR CAG repeats was associated with HDL cholesterol (HDL-C) concentration, and the stepwise multiple regression model showed that this association was independent of body mass index (BMI), triglycerides (TG) and total cholesterol (TC), although these factors influence HDL-C concentration. Furthermore, men with <22 vs men with ≥22 CAG repeats showed higher blood pressure and higher prevalence of hypertension. Shorter CAG repeat numbers were associated with the increased risk of hypertension in a multivariate logistic regression analysis (odds ratio=0·715; 95% confidence interval, 0·517-0·989; P=0·043). No significant correlation of AR CAG repeat polymorphism with sex hormone levels, TG, LDL cholesterol (LDL-C) or TC was found. This study provides evidence that men carrying shorter (<22) AR CAG repeats have lower HDL-C level and increased risk of hypertension. The androgenic activity may differ due to the polymorphic length of CAG repeats of the AR gene.

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.

The role of testosterone in coordinating male life history strategies: The moderating effects of the androgen receptor CAG repeat polymorphism

Partnered fathers often have lower testosterone than single non-parents, which is theorized to relate to elevated testosterone (T) facilitating competitive behaviors and lower T contributing to nurturing. Cultural- and individual-factors moderate the expression of such psychobiological profiles. Less is known about genetic variation's role in individual psychobiological responses to partnering and fathering, particularly as related to T. We examined the exon 1 CAG (polyglutamine) repeat (CAGn) within the androgen receptor (AR) gene. AR CAGn shapes T's effects after it binds to AR by affecting AR transcriptional activity. Thus, this polymorphism is a strong candidate to influence individual-level profiles of “androgenicity.” While males with a highly androgenic profile are expected to engage in a more competitive-oriented life history strategy, low androgenic men are at increased risk of depression, which could lead to similar outcomes for certain familial dynamics, such as marriage stability and parenting. Here, in a large longitudinal study of Filipino men (n=683), we found that men who had high androgenicity (elevated T and shorter CAGn) or low androgenicity (lower T and longer CAGn) showed elevated likelihood of relationship instability over the 4.5-year study period and were also more likely be relatively uninvolved with childcare as fathers. We did not find that CAGn moderated men's T responses to the fatherhood transition. In total, our results provide evidence for invested fathering and relationship stability at intermediate levels of androgenicity and help inform our understanding of variation in male reproductive strategies and the individual hormonal and genetic differences that underlie it.

Androgen receptor CAG repeat polymorphism and hypothalamic‐pituitary‐gonadal function in Filipino young adult males

Testosterone (T), the primary androgenic hormone in males, is stimulated through pulsatile secretion of LH and regulated through negative feedback inhibition at the hypothalamus and pituitary. The hypothalamic-pituitary-gonadal (HPG) axis also controls sperm production through the secretion of follicle-stimulating hormone (FSH). Negative feedback in the HPG axis is achieved in part through the binding of T to the androgen receptor (AR), which contains a highly variable trinucleotide repeat polymorphism (AR-CAGn). The number of repeats in the AR-CAGn inversely correlates with transcriptional activity of the AR. Thus, we predicted longer AR-CAGn to be associated with higher T, LH, and FSH levels. We examined the relationship between AR-CAGn and total plasma T, LH, and FSH, as well as "bioavailable" morning (AM-T) and evening (PM-T) testosterone in 722 young (21.5 ± 0.5 years) Filipino males. There was no relationship between AR-CAGn and total T, AM-T, or LH (P > .25 for all). We did observe a marginally non-significant (P = .066) correlation between AR-CAGn and PM-T in the predicted direction, and a negative correlation between AR-CAGn and FSH (P = .005). Our results both support and differ from previous findings in this area, and study parameters that differ between our study and others, such as participant age, sample time, and the role of other hormones should be considered when interpreting our findings. While our data point to a modest effect of AR-CAGn on HPG regulation at best, the AR-CAGn may still affect somatic traits by regulating androgenic activity at peripheral tissues.

Androgen receptor gene polymorphism influence fat accumulation: A longitudinal study from adolescence to adult age.

To determine the influence of androgen receptor CAG and GGN repeat polymorphisms on fat mass and maximal fat oxidation (MFO), CAG and GGN repeat lengths were measured in 128 young boys, from which longitudinal data were obtained in 45 of them [mean ± SD: 12.8 ± 3.6 years old at recruitment, and 27.0 ± 4.8 years old at adult age]. Subjects were grouped as CAG short (CAGS ) if harboring repeat lengths ≤ 21, the rest as CAG long (CAGL ); and GGN short (GGNS ) if GGN repeat lengths ≤ 23, or long if > 23 (GGNL ). CAGS and GGNS were associated with lower adiposity than CAGL or GGNL (P < 0.05). There was an association between the logarithm of CAG repeats polymorphism and the changes of body mass (r = 0.34, P = 0.03). At adult age, CAGS men showed lower accumulation of total body and trunk fat mass, and lower resting metabolic rate (RMR) and MFO per kg of total lean mass compared with CAGL (P < 0.05). GGNS men also showed lower percentage of body fat (P < 0.05). In summary, androgen receptor CAG and GGN repeat polymorphisms are associated with RMR, MFO, fat mass, and its regional distribution in healthy male adolescents, influencing fat accumulation from adolescence to adult age.

Androgen receptor CAG and GGN repeat polymorphisms influence performance in boys and girls.

Shorter CAG and GGN androgen receptor (AR) repeat polymorphisms are associated with stronger androgen signaling, and therefore, could influence lean mass and exercise performance during growth. Physical fitness and body composition were measured by standardized procedures and the length of CAG and GGN repeats was determined by PCR and fragment analysis in 152 boys (11.5±2.6 years; Tanner ≤5) and 116 girls (10.1±3.2 years; Tanner ≤5). Individuals were grouped as CAG short (CAGS) if harboring repeat lengths of ≤21 and CAG long (CAGL) if CAG >21. Moreover, subjects were grouped as GGN short (GGNS) if harboring repeat lengths of ≤23 and GGN long (GGNL) if GGN>23. No significant differences in anthropometrics and body composition were observed between either CAGS and CAGL groups and GGNS and GGNL groups. Boys harboring CAGS completed the 300-meter test faster than their CAGL counterparts. Moreover, girls from the GGNL group showed a significant higher VO2max than those in the GGNS group. In summary, carrying a short allele of the androgen receptor CAG repeat polymorphism is associated to higher anaerobic performance in boys, whereas long alleles of androgen receptor GGN polymorphisms are associated to higher aerobic capacity in girls.

Androgen receptor CAG repeat length and estrogen receptor status in postmenopausal breast cancer prognosis.

The influence of the androgen receptor (AR) CAG repeat polymorphism on breast cancer is controversial. We investigated the combined effects of CAG repeat length and estrogen receptor (ER) status on prognosis in 355 postmenopausal women with primary breast cancer. CAG repeat length was determined by the HUMARA test. Relapse-free survival (RFS) and overall survival (OS) according to the X-weighted CAG repeat biallelic mean (XWBM) were investigated by univariate and multivariate analysis. XWBM was not associated with RFS or OS, but a significant interaction between XWBM and ER status (p = 0.002) was found for OS. ER-negative patients with median XWBM &lt;20 showed lower OS than ER-negative/XWBM ≥20 patients (HR = 0.270; 95% Cl: 0.073-0.999). ER-negative/XWBM &lt;20 patients also had significantly lower OS than ER-positive women, irrespective of CAG repeat length (p&lt;0.001). Accordingly, estimated OS was lowest in ER-negative patients with XWBM &lt;20 (OS: 0.63, 95% CI: 0.41-0.79) and highest in ER-positive patients with XWBM &lt;20 (OS: 0.95, 95% CI: 0.90-0.97). Our data suggest that short CAG repeat length is associated with increased risk of death in ER-negative disease but is related to better survival when ER is expressed. These findings are in agreement with the hypothesis that AR may stimulate or inhibit breast cancer growth depending on ER status, AR transactivation, and the endocrine-metabolic environment of breast tumors. Evaluation of CAG repeat length together with ER status could help improve the estimation of the risk of death, with possible implications for the optimization of standard breast cancer treatment and implementation of prevention strategies.

Association of androgen receptor CAG repeat polymorphism and risk of epithelial ovarian cancer

Biological and epidemiologic evidence suggested that androgen and its receptor may play an important role in ovarian carcinogenesis. However, results of previous association studies about ovarian cancer and AR CAG repeat polymorphism were inconsistent. Furthermore, none of these studies were conducted in Asians. We evaluated the relationship between AR CAG repeat length and epithelial ovarian cancer (EOC) risk among a Chinese population including 1800 pathologically confirmed EOC patients and 1800 frequency matched controls. Women with longer AR CAG repeats had a decreased EOC risk (OR=0.87 for per CAG_A increase, 95% CI: 0.81-0.95). Compared to those with shorter (<22) CAG_A repeat length, women with of longer (≥22) CAG_A repeats had a 34% decreased EOC risk (OR=0.66, 95% CI: 0.57-0.75). For CAG_S and CAG_L, the results remained consistent. Our findings suggest that androgen signaling contributes to the development of ovarian cancer.

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.

Genetic factors associated with exercise performance in atmospheric hypoxia.

Background and Objective‘Natural selection’ has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations.Criteria for considering studies for this reviewAll studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using ‘nitrogen dilution of oxygen’ (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review.Search strategy for identification of studiesTwo electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English.Data collection and analysisStudies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies.ResultsA total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ( dot{V} O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case–control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies.ConclusionThe small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40279-015-0309-8) contains supplementary material, which is available to authorized users.

Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action.

In the last decade, ample evidence has demonstrated the growing importance of androgen receptor (AR) CAG repeat polymorphism in andrology. This genetic parameter is able to condition the peripheral effects of testosterone and therefore to influence male sexual function and fertility, cardiovascular risk, body composition, bone metabolism, the risk of prostate and testicular cancer, the psychiatric status, and the onset of neurodegenerative disorders. In this review, we extensively discuss the literature data and identify a role for AR CAG repeat polymorphism in conditioning the systemic testosterone effects. In particular, our main purpose was to provide an updated text able to shed light on the many and often contradictory findings reporting an influence of CAG repeat polymorphism on the targets of testosterone action.

Effects of testosterone replacement therapy on bone metabolism in male post-surgical hypogonadotropic hypogonadism: focus on the role of androgen receptor CAG polymorphism

The relationship between androgen receptor (AR) CAG polymorphism and bone metabolism is highly controversial. We, therefore, aimed to evaluate the independent role of AR CAG repeat polymorphism on bone metabolism improvement induced by testosterone replacement therapy (TRT) in male post-surgical hypogonadotropic hypogonadism, a condition frequently associated with hypopituitarism and in which the effects of TRT have to be distinguished from those resulting from concomitant administration of pituitary function replacing hormones. 12 men affected by post-surgical hypogonadotropic hypogonadism [mean duration of hypogonadism 8.3 ± 2.05 (SD) months] were retrospectively assessed before and after TRT (from 74 to 84 weeks after the beginning of therapy). The following measures were studied: parameters of bone metabolism [serum markers and bone mineral density (BMD)], pituitary dependent hormones and genetic analysis (AR CAG repeat number). Total testosterone, estradiol, free T4 (FT4) and insulin-like growth factor-1 (IGF-1) increased between the two phases, while follicle stimulating hormone (FSH) decreased. While serum markers did not vary significantly between the two phases, BMD improved slightly but significantly in all the studied sites. The number of CAG triplets correlated negatively and significantly with all the variations (Δ-) of BMDs. Conversely, Δ-testosterone correlated positively and significantly with all studied Δ-BMDs, while Δ-FSH, Δ-estradiol, Δ-FT4, and Δ-IGF-1 did not correlate significantly with any of the Δ-BMDs. Multiple linear regression analysis, after correction for Δ-testosterone, showed that CAG repeat length was negatively and significantly associated with ∆-BMD of all measured sites. Our data suggest that, in post-surgical male hypogonadotropic hypogonadism, shorter AR CAG tract is independently associated with greater TRT-induced improvement of BMD.

Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study

This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAGS) if they harbored repeat length of ≤20 or as CAG long (CAGL) if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified physicians; CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) method; and the serum levels of the sex hormones were detected by radioimmunoassay. Student's t-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T) level was positively associated with the AR CAG repeat length (P = 0.01); whereas, no significant correlation of T or AR CAG repeat polymorphism with the penile length was found (P = 0.593). Interestingly, an inverse association was observed between serum prolactin (PRL) levels and penile length by linear regression analyses (β= −0.024, P = 0.039, 95% confidence interval (CI): −0.047, 0). Collectively, this study provides the first evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.

The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study

The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables. To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study. Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study. Outpatient study recruiting from secondary and primary care. A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study. Testosterone 2% transdermal gel vs placebo. Regression coefficient of AR CAG from linear regression models for each variable. AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity. AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

Mental rotation in intellectually gifted boys is affected by the androgen receptor CAG repeat polymorphism

Testosterone was shown to organize brain and modulate cognitive functions. It is currently unknown whether mental rotation is also associated with prenatal testosterone exposure and testosterone-related genetic polymorphisms. The aim of our study was to analyze associations between mental rotation performance, the actual testosterone levels, the prenatal testosterone level (expressed as 2D:4D ratio) and the androgen receptor CAG repeat polymorphism in intellectually gifted boys. One hundred forty-seven boys aged 10–18 years with IQ>130 were enrolled. Saliva samples were collected and used for ELISA of actual levels of salivary testosterone. The 2D:4D finger length ratio as an indicator of prenatal testosterone was measured on both hands and averaged. Amthauer mental rotation test was used for the assessment of this spatial ability. The CAG repeat polymorphism in the androgen receptor gene was analyzed using PCR and capillary electrophoresis. Linear regression revealed that 2D:4D finger length ratio and the number of CAG repeats in the androgen receptor gene were associated with mental rotation. Actual levels of testosterone did not correlate significantly with mental rotation. Multivariate analysis of covariance revealed that after adjustment of age as a confounding variable, only the effect of the genetic polymorphism was significant. The results are in line with our previous genetic analysis of intellectually gifted boys showing the importance of CAG repeat polymorphism in the androgen receptor gene. Details of the interactions between androgen signaling, testosterone levels and its metabolism especially during the prenatal development of brain function remain to be elucidated.