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.

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 androgen receptor gene CAG repeat length polymorphism in pubertal gynecomastia.

OBJECTIVES: Androgen receptor gene CAG repeat, AR (CAG)n, polymorphism is thought to have an effect on male reproductive functions and a relationship between long AR (CAG)n and decreased androgenic activity has been shown. Therefore, we hypothesized that in adolescents with long AR CAG repeat the prevalence of pubertal gynecomastia (PG) will be higher and we aimed to investigate the association between AR (CAG)n polymorphism and PG in Turkish adolescents. METHODS: Adolescents with PG between 11 and 19 years of age were enrolled as the study group and healthy individuals without a history of PG, who were at least 14 years of age and Tanner 4 or 5 were enrolled as the control group. The AR (CAG)n length was detected by direct DNA sequencing analysis and reproductive hormones were measured by standardized analyses. RESULTS: The mean AR (CAG)n was 22.3 ± 2.6 (mean ± SD) in the PG group (n=101) and 21.9 ± 3.1 (mean ± SD) in the control group (n=88) (p=0.276). The adolescents with short AR (CAG)n had lower body mass index standard deviation scores (BMI SDS) compared to the adolescents with intermediate and long repeat numbers (p=0.029). CONCLUSIONS: The results of this study showed a lack of direct association between AR (CAG)n and PG. However, the significant relationship between the AR (CAG)n quartiles and BMI SDS suggests that long AR (CAG)n might cause PG indirectly. Further studies are needed to better clarify this relationship.

Analysis of the CAG tract length in the Androgen Receptor gene in Mexican patients with nonsyndromic cryptorchidism.

OBJECTIVES: Cryptorchidism is the most common genitourinary birth defect in live newborn males and is considered as an important risk factor for testicular germ cell tumors and infertility. The Androgen Receptor gene is important in this pathology due to its participation, mainly, in the inguinoscrotal phase of testicular descent. We determine the length of the CAG tract in the Androgen Receptor (AR) gene in Mexican patients with nonsyndromic cryptorchidism. METHODS: One hundred and 15 males were included; of these, 62 had nonsyndromic cryptorchidism and 53 were healthy volunteers. DNA was extracted from a peripheral blood samples, subsequently, the CAG tract in exon 1 of AR gene was amplified by PCR and sequenced. RESULTS: Mexican patients with nonsyndromic cryptorchidism presented 25.03 ± 2.58 repeats of CAG tract in the AR gene compared to 22.72 ± 3.17 repeats of CAG tract in Mexican healthy individuals (p≤0.0001; t value of 4.3). Furthermore, the deletion of codon 57 that corresponds to the deletion of a leucine residue at position 57 (Del L57) in the AR gene was found for the first time in a nonsyndromic cryptorchidism patient. This molecular alteration has been related previously to testicular germ cell tumor (TGCT). CONCLUSIONS: The CAG tract in the AR gene is longer in patients with nonsyndromic cryptorchidism than in healthy individuals, supporting the association between this polymorphism of the AR gene and nonsyndromic cryptorchidism in the Mexican population.

Exogenous testosterone increases status-seeking motivation in men with unstable low social status.

Testosterone is associated with status-seeking behaviors such as competition, which may depend on whether one wins or loses status, but also on the stability of one's status. We examined (1) to what extent testosterone administration affects competition behavior in repeated social contests in men with high or low rank, and (2), whether this relationship is moderated by hierarchy stability, as predicted by the status instability hypothesis. Using a real effort-based design in healthy male participants (N = 173 males), we first found that testosterone (vs. placebo) increased motivation to compete for status, but only in individuals with an unstable low status. A second part of the experiment, tailored to directly compare stable with unstable hierarchies, indicated that exogenous testosterone again increased competitive motivation in individuals with a low unstable status, but decreased competition behavior in men with low stable status. Additionally, exogenous testosterone increased motivation in those with a stable high status. Further analysis suggested that these effects were moderated by individuals' trait dominance, and genetic differences assessed by the androgen receptor (CAG-repeat) and dopamine transporter (DAT1) polymorphisms. Our study provides evidence that testosterone specifically boosts status-related motivation when there is an opportunity to improve one's social status. The findings contribute to our understanding of testosterone's causal role in status-seeking motivation in competition behavior, and indicate that testosterone adaptively increases our drive for high status in a context-dependent manner. We discuss potential neurobiological pathways through which testosterone may attain these effects on behavior.

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.

Implicancias del polimorfismo de repeticiones de glutamina del receptor de andrógenos en la presentación de eventos peripuberales / Implications of androgen receptor gene glutamine repeat polymorphism in the presentation of peripubertal events

Puberty is a period of transition during which girls and boys acquire secondary sexual characteristics and reproductive capacity. The order of appearance of the pubertal traits accounts for a correct or otherwise incorrect activation of the hypothalamic-pituitary-gonadal axis. The growth of the pubic hair before 8 years in girls and 9 years in boys (precocious pubarche, PP) without any other apparent cause has been largely attributed to the early increase of adrenal androgen levels. Also, premature adrenarche (PA) was traditionally considered an extreme within the normal range, however emerging evidence links early androgen excess with the metabolic syndrome. In this context, it has been suggested that an exacerbated clinical manifestation of androgens may be related to greater sensitivity of the androgen receptor (AR). The purpose of this review is to summarize the current knowledge of the contribution of the CAG repeats polymorphisms of AR in the peripubertal manifestations of androgens with special emphasis on precocious pubarche and body composition

CAG repeat polymorphisms in the androgen receptor and breast cancer risk in women: a meta-analysis of 17 studies.

The association between polymorphic CAG repeats in the androgen receptor gene in women and breast cancer susceptibility has been studied extensively. However, the conclusions regarding this relationship remain conflicting. The purpose of this meta-analysis was to identify whether androgen receptor CAG repeat lengths were related to breast cancer susceptibility. The MEDLINE, PubMed, and EMBASE databases were searched through to December 2014 to identify eligible studies. Data and study quality were rigorously assessed by two investigators according to the Newcastle-Ottawa Quality Assessment Scale. The publication bias was assessed by the Begg's test. Seventeen eligible studies were included in this meta-analysis. The overall analysis suggested no association between CAG polymorphisms and breast cancer risk (odds ratio [OR] 1.031, 95% confidence interval [CI] 0.855-1.245). However, in the subgroup analysis, we observed that long CAG repeats significantly increased the risk of breast cancer in the Caucasian population (OR 1.447, 95% CI 1.089-1.992). Additionally, the risk was significantly increased in Caucasian women carrying two alleles with CAG repeats ≥22 units compared with those with two shorter alleles (OR 1.315, 95% CI 1.014-1.707). These findings suggest that long CAG repeats increase the risk of breast cancer in Caucasian women. However, larger scale case-control studies are needed to validate our results.

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.

CAG repeat testing of androgen receptor polymorphism: is this necessary for the best clinical management of hypogonadism?

INTRODUCTION: It is controversial whether or not testing the length of the androgen receptor polymorphism in clinical practice is useful for correct diagnosis and treatment of hypogonadism. AIM: To describe the molecular and clinical implications of testing the length of the androgen receptor polymorphism for treatment of hypogonadism in both male and female subjects. METHODS: A systematic Medline search was conducted using several terms related to and including the terms "androgen receptor," "CAG-repeat polymorphism," "male hypogonadism," "female hypogonadism," and "neurodegenerative disease." MAIN OUTCOME MEASURES: Clinical evidence that demonstrates the importance of CAG repeat number investigation in male and female hypogonadism. RESULTS: A thorough review of the clinical utility of CAG repeat polymorphism investigation in men and women with hypogonadism is presented. CONCLUSIONS: The role of AR CAG repeat number investigation in hypogonadism (male and female) is not yet established in the clinical practice. In both sexes, a role during clinical management of hormonal replacement therapies may be hypothesized, but the CAG repeat number's relationship with the presence or absence of hypogonadal symptoms remains unclear. Pharmacogenomic investigations of the AR polymorphism may be a future option to tailor testosterone titration individually and to better identify subjects as potentially more or less responsive to treatments; also, investigation may be important to individually predict beneficial and side effects in special subpopulations, specifically, obese men and postmenopausal women.

The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS.

Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis. Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.

Lack of Influence of the Androgen Receptor Gene CAG-Repeat Polymorphism on Clinical and Electrocardiographic Manifestations of the Brugada Syndrome in Man.

BACKGROUND: Clinical studies suggest that testosterone (T) plays an important role in the male predominance of the clinical manifestations of the Brugada syndrome (BS). However, no statistically significant correlations have been observed between T levels and electrocardiogram (ECG) parameters in the BS patients. We investigated whether the hormonal pattern and the variation within CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene, affecting androgen sensitivity, are associated with the Brugada ECG phenotype in males. METHODS AND RESULTS: 16 male patients with BS (mean age 45.06 ± 11.3 years) were studied. 12-lead ECG was recorded. Blood levels of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free-T, dihydrotestosterone, 17-ß-estradiol, estrone, 3-alpha-androstanediol-glucuronide, delta-4-androstenedione, dehydroepiandrosterone sulphate, progesterone, 17-hydroxyprogesterone, and sex hormone binding globulin were assayed. Genotyping of CAG repeats on DNA extracted from leukocytes was carried out. No relationship was found between hormone values and ECG parameters of BS. BS patients showed the CAG length normally recognized in the human polymorphism range and the number of CAG repeats did not correlate with the ECG pattern of BS. CONCLUSIONS: The AR CAG repeat length does not correlate with the ECG features of the patients affected by BS. The search for genes downstream AR activation as possibly responsible for the increased risk of spontaneous arrhythmias in BS males after puberty is warranted.

Relation of CAG Repeat Polymorphism of AR Gene in Men of Han Nationality from Northern China to the Effectiveness of Hypoxic Training / 中国运动医学杂志

Objective To investigate the distribution characteristics of (CAG)n polymorphism in the exonl of the androgen receptor (AR) gene and its relation to the sensitivity of hypoxic training in men of Han nationality from northern China. Methods Sixty five healthy young men of Han nationality completed HiHiLo training under simulated normobaric hypoxic environment for 4 weeks. They stayed under the condition of 14.3-14.8% O_2 (simulating 2800～3000m) during nighttime and carried out hypoxic training under the condition of 14.8-15.4% O_2 (simulating 2500～2800m) 3 times per week at the intensity of 75% individual VO_2max. VO_2max and body weight of the subjects were measured. GeneScan method was used to identify the repeat alleles (genotypes) of CAG polymorphism. Results (1) Fifteen alleles (CAG)12,(CAG)16-28,(CAG)30 repeat alleles (genotypes) were observed in the subjects, in which (CAG)22 was the most common allele; (2) When 21 and 22 alleles were used as the cut point, the baseline of body weight in those carrying shorter genotypes was significantly lower than that in those carrying longer genotypes; (3) △VO_2max and △rVO_2max in men carrying shorter genotypes were significantly higher than that in men carrying longer genotypes after hypoxic training. Conclusion The result reveals that AR (CAG)n polymorphism is associated with the sensitivity of simulated normobaric hypoxic HiHiLo training in men of Han nationality from northern China, especially in those carrying shorter genotypes of AR CAG.

Preliminary study of relationship between the CAG repeat polymorphism of androgen receptor gene and benign prostatic hyperplasia in Xinjiang Uygur men / 中华泌尿外科杂志

0.05).But the association between (CAG)n repeats and prostate volume was significant (P