Androgen Receptor - NutraPedia

Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men

Background: Low vitality is a common symptom of testosterone deficiency; however, clinical trial results remain inconclusive regarding the responsiveness of this symptom to hormone replacement. Aim: The aim of the present study was to determine if the relationship between circulating testosterone levels and vitality would be moderated by the CAG repeat length in the androgen receptor (AR) gene, which influences the receptor's sensitivity to testosterone. Methods: We examined 676 men in the Vietnam Era Twin Study of Aging when they were, on average, 55.4 years old (SD = 2.5). Salivary testosterone levels were measured by using 3 samples collected at waking on 3 nonconsecutive days. The average testosterone level was classified as low, normal, or high based on 1-SD cutoffs. Analyses were conducted using multilevel, mixed linear models, which accounted for the nonindependence of the twin data, and adjusted for the effects of age, ethnicity, BMI, chronic health conditions, depressive symptoms, and sleep quality. Outcomes: Vitality was measured using the 36-item Short Form (SF-36) vitality subscale. Results: We observed a significant interaction between salivary testosterone and the AR-CAG repeat length. When the repeat length was short, men with low testosterone had significantly lower vitality. As the AR-CAG repeat length increased, the magnitude of the testosterone effect decreased. Clinical translation: The observed interaction between testosterone and variation in the AR gene suggests that men with more sensitive ARs, as indicated by a shorter AR-CAG repeat, are more likely to experience symptoms of age-related testosterone deficiency. Strengths & limitations: Strengths of the present study include our use of a large community-based sample, the use of multiple testosterone measurements, and the availability of a comprehensive set of covariates that may impact the association of interest. Limitations include the homogeneous nature of the sample with respect to ethnicity, the brevity of the 36-item Short Form vitality subscale, and our inability to establish change in testosterone levels because of the cross-sectional nature of data. Conclusions: The association between testosterone and vitality appears to be clinically meaningful and is in part dependent on variation in the AR gene. Panizzon MS, Bree K, Hsieh T-C, et al. Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men. J Sex Med 2020;17:2351-2361.

Functional in vitro characterisation of the androgen receptor GGN polymorphism

Superior androgen receptor (AR) function in subjects carrying a GGN repeat length of 23 (GGN23) has been indicated in vivo. Therefore, the activity of the AR carrying GGN23 combined with CAG22 was compared to the AR with GGN10, 24 and 27, respectively, in the presence of 0.1-100 nM testosterone or DHT. At 100 nM DHT, GGN24 showed 35% lower transactivating activity (95% [CI]: 20-50%) than GGN23. GGN10 and GGN27 also showed significantly less AR activity than GGN23 (mean differences [95% CI]: 54% [40-68%] and 58% [39-78%], respectively). The same trend was also observed at lower DHT concentrations. In response to R1881, GGN23 activity was significantly higher than for other lengths. ARs with other glutamine numbers than 23 have lower transactivating capacity in response to both testosterone and DHT. Congenital malformations and other signs of hypoandrogenism in subjects with AR gene GGN lengths other than 23 could, hence, be related to a lower AR activity.

Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne

Background: The androgen receptor (AR) is a structurally conserved member of the nuclear receptor superfamily. The amino-terminal domain is required for transcriptional activation and contains a region of polyglutamine encoded by CAG trinucleotide repeats. In humans, the number of CAG repeats is polymorphic. Expansion of CAG repeats in the AR has clinical implications for human disease. Objective: Androgens influence androgenetic alopecia (AGA), hirsutism, and acne; the polymorphisms in CAG repeat length may affect the clinical course of patients with these cutaneous disorders. The purpose of this study is to test for an association between these disorders and CAG repeat length. Methods: We analyzed normal lymphocyte genomic DNA from a total of 48 men and 60 women. The CAG repeat region of the AR was amplified by polymerase drain reaction (PCR) and the products were sized on polyacrylamide gels. Results: In normal men and women controls, a range of 12 to 29 trinucleotide repeats was found, with men having 22 +/- 4 (M 6 SD), women 21 +/- 3. Men with AGA had 19 +/- 3, whereas women with AGA had 17 +/- 3. Men with acne had 21 +/- 3, whereas women had 20+/- 3; men with AGA and acne had 18 +/- 4; and women with hirsutism had 16 +/- 3. Women with a combination of at least two disorders also had 16 +/- 3 trinucleotide repeats. Conclusion: associated with the development of androgen-mediated skin disorders in men and women. These data suggest that CAG-repeat length in AR may affect androgen mediated gene expression in hair follicles and sebaceous glands in men and women with these androgenic skin disorders.

Relationship between the CAG repeat polymorphism in the androgen receptor gene and acne in the Han ethnic group

Background: The modulatory domain of the human androgen receptor (AR) gene contains a polymorphic CAG repeat coding for a polyglutamine tract which is inversely correlated with transcriptional activity of the AR. Androgens acting through the AR play a crucial role in the pathogenesis of acne vulgaris. We therefore investigated the relationship between CAG repeat polymorphism in the AR gene and acne susceptibility. Methods: 206 acne patients and 200 controls participated in the study. Genomic DNA was extracted from peripheral blood lymphocytes of individual patients, and the CAG repeat region was amplified by polymerase chain reaction (PCR) using fluorescence-labeled primers. Samples were then run on an ABI 377 gene scan analysis gel with an internal molecular-weight marker. Ten male samples were chosen randomly for sequencing to confirm the number of CAG repeats. The 2-sample independent t test was used to analyze the data. Results: The mean number of the CAG repeat in the AR was 22.07 (14-28) in the controls and 20.61 (13-26) in the male acne group. There was a significant correlation between the CAG repeat length and male acne. No significant difference was observed between female patients and their controls. Conclusion: The results suggest that the AR gene CAG repeat polymorphism may be one of the candidate genetic markers for male acne susceptibility in the Han population.

Influence of Androgen Receptor Gene CAG and GGC Polymorphisms on Male Sexual Function: A Cross-Sectional Study

Background. No study has assessed the possible involvement of GGC androgen receptor (AR) polymorphism in sexual function. Our aim is to evaluate the association between CAG and GGC AR polymorphisms in this function. Methods. We retrospectively examined eighty-five outpatients. Clinical, biochemical, and genetic parameters were considered. Sexual assessment was performed using the International Index of Erectile Function (IIEF) which evaluates erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction (OS). Results. In the whole sample, CAG repeats were inversely correlated with EF, OF, and total IIEF-15 score, whereas GGC tracts did not show any significant correlation with sexual function. CAG relationship with IIEF items retained significance only in the eugonadal but not in the hypogonadal cohort. On the other hand, GGC tracts were not found to be significantly correlated with IIEF variables in either eugonadal or hypogonadal subjects. In eugonadal subjects, logistic regression pointed out that a higher number of CAG triplets were associated with lower values of EF, OF, SD, OS, and total IIEF independently from other confounders. Conclusions. GGC polymorphism seems not to exert any influence on sexual function, whereas CAG polymorphism appears to affect sexual parameters only in eugonadal subjects.

Effectiveness of finasteride on patients with male pattern baldness who have different androgen receptor gene polymorphism

Finasteride is not necessarily effective on all of the male pattern baldness (MPB) patients. To know any factor which correlates with the effectiveness of finasteride, the polymorphism of androgen receptor (AR) gene was analyzed. Symptoms of the 488 MPB patients (18-62 y) before and after treatment with total dose of 10 mg or more of finasteride was typed by photographic method. The number of CAG and GGC repeats in AR gene of MPB patients was determined by DNA sequencing. When the number of the triplet repeats (CAG + GGC) was plotted against the degree of symptom improvement after treatment with this drug, a broad correlation between these variables was observed. The smaller the repeat number, the higher the improvement with finasteride. The group of patients with shorter repeat region in AR gene responded better to this drug than that with longer repeat region, although the former patients tended to reveal severe initial symptoms. Determination of such polymorphism is thought to be useful in the drug choice for MPB patients.

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.

Testosterone and the brain: from cognition to autism

Sex and gender matter in all aspects of life. Humans exhibit sexual dimorphism in anatomy, physiology, but also pathology. Many of the differences are due to sex chromosomes and, thus, genetics, other due to endocrine factors such as sex hormones, some are of social origin. Over the past decades, huge number of scientific studies have revealed striking sex differences of the human brain with remarkable behavioral and cognitive consequences. Prenatal and postnatal testosterone influence brain structures and functions, respectively. Cognitive sex differences include especially certain spatial and language tasks, but they also affect many other aspects of the neurotypical brain. Sex differences of the brain are also relevant for the pathogenesis of neuropsychiatric disorders such as autism spectrum disorders, which are much more prevalent in the male population. Structural dimorphism in the human brain was well-described, but recent controversies now question its importance. On the other hand, solid evidence exists regarding gender differences in several brain functions. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences in healthy individuals and people in the autism spectrum.

AR CAG repeat length is not associated with serum gonadal steroids and lipid levels in healthy men

Cardiovascular risk factors seem to be affected by androgens, which exert their action through the androgen receptor (AR). Androgenic action correlates inversely with a polymorphic CAG repeat region in the AR gene encoding for glutamine residues the length of which appears to influence high density lipoprotein (HDL) cholesterol levels. The aim of the study was to investigate the possible association between AR gene polymorphism and serum sex steroids and lipids. 170 healthy males, aged 22-59 years (mean 42 years), were included in the study. Anthropometrical as well as sociometrical parameters were recorded. Body fat content (BFC) (% fat mass) was measured by bioelectrical impedance. Serum lipids and total and free testosterone (T) and estradiol (E(2)) levels were measured in each subject. AR gene CAG repeats length was determined. No significant correlation was found between the length of AR gene polyglutamine tract and the levels of gonadal steroids (total and free T, total and free E(2)) or to the lipid levels (Triglycerides, total, HDL and LDL cholesterol). In addition, serum lipid levels were not significantly different in the lower compared to higher half of CAG repeats length distribution. On multiple regression analysis BFC was found to predict HDL-cholesterol and triglycerides were found to show, respectively, significant negative and positive correlation with body fat content. In conclusion, AR gene polymorphism may not predict sex steroid levels in healthy males. Possible impact of CAG repeats length on lipids profile has not been established.

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.

Testosterone and androgen receptor gene polymorphism are associated with confidence and competitiveness in men

A contribution to a special issue on Hormones and Human Competition. Studies in non-human animals and humans have demonstrated the important role of testosterone in competitive interactions. Here, we investigated whether endogenous testosterone levels predict the decision to compete, in a design excluding spite as a motive underlying competitiveness. In a laboratory experiment with real monetary incentives, 181 men solved arithmetic problems, first under a noncompetitive piece rate, followed by a competition incentive scheme. We also assessed several parameters relevant to competition, such as risk taking, performance, and confidence in one's own performance. Salivary testosterone levels were measured before and 20min after the competition task using mass spectrometry. Participants were also genotyped for the CAG repeat polymorphism of the androgen receptor gene, known to influence the efficacy of testosterone signaling in a reciprocal relationship to the number of CAG repeats. We observed a significant positive association between basal testosterone levels and the decision to compete, and that higher testosterone levels were related to greater confidence in one's own performance. Whereas the number of CAG repeats was not associated with the choice to compete, a lower number of CAG repeats was related to greater confidence in those who chose to compete, but this effect was attributable to the polymorphism's effect on actual performance. An increase in testosterone levels was observed following the experiment, and this increase varied with self-reported high-school math grades. We expand upon the latest research by documenting effects of the androgen system in confidence in one's own ability, and conclude that testosterone promotes competitiveness without spite.

Baldness and the androgen receptor: the AR polyglycine repeat polymorphism does not confer susceptibility to androgenetic alopecia

Androgenetic alopecia, or male pattern baldness, is a complex condition with a strong heritable component. In 2001, we published the first significant evidence of a genetic association between baldness and a synonymous coding SNP (rs6152) in the androgen receptor gene, AR. Recently, this finding was replicated in three independent studies, confirming an important role for AR in the baldness phenotype. In one such replication study, it was claimed that the causative variant underlying the association was likely to be the polyglycine (GGN) repeat polymorphism, one of two apparently functional triplet repeat polymorphisms located in the exon 1 transactivating domain of the gene. Here, we extend our original association finding and present comprehensive evidence from approximately 1,200 fathers and sons drawn from 703 families of the Victorian Family Heart Study, a general population Caucasian cohort, that neither exon 1 triplet repeat polymorphism is causative in this condition. Seventy-eight percent of fathers (531/683) and 30% of sons (157/520) were affected to some degree with AGA. We utilised statistical methods appropriate for the categorical nature of the phenotype and familial structure of the cohort, and determined that whilst SNP rs6152 was strongly associated with baldness (P < 0.0001), the GGN triplet repeat was not (P = 0.13). In the absence of any other known common functional coding variants, we argue that the causative variant is likely to be in the non-coding region, and yet to be identified. The identification of functional non-coding variants surrounding AR may have significance not only for baldness, but also for the many other complex conditions that have thus far been linked to AR.

The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels

Introduction: In addition to a depletion of androgen, attenuated action of androgen receptor (AR) might also contribute to andropausal symptoms. Aim: To evaluate the interaction of AR cytosine adenine guanine (CAG) repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. Methods: From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan. All participants received physical examination, answered questionnaires to collect their demographic information and medical histories, completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire, and provided 20-cm(3) whole blood samples for biochemical and genetic evaluation. Main outcome measures: The ADAM questionnaire was used to evaluate andropausal symptoms. 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. Results: Seven hundred two men with the mean age of 57.2 ± 6.5 years were included. There was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. When TT levels were above 340 ng/dL, subjects with AR CAG repeat lengths ~25 showed significantly higher risk of developing andropausal symptoms, as compared with those with AR CAG repeat lengths ~22 (P = 0.006), but this was not observed when TT levels were 340 ng/dL or below. Age and number of comorbidities were also independent risk factors for andropausal symptoms. Conclusion: In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing andropausal symptoms. Age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested.

Androgen receptor gene polymorphisms lean mass and performance in young men

The exon-1 of the androgen receptor (AR) gene contains two repeat length polymorphisms which modify either the amount of AR protein inside the cell (GGN(n), polyglycine) or its transcriptional activity (CAG(n), polyglutamine). Shorter CAG and/or GGN repeats provide stronger androgen signalling and vice versa. To test the hypothesis that CAG and GGN repeat AR polymorphisms affect muscle mass and various variables of muscular strength phenotype traits, the length of CAG and GGN repeats was determined by PCR and fragment analysis and confirmed by DNA sequencing of selected samples in 282 men (28.6 ± 7.6 years). Individuals were grouped as CAG short (CAG(S)) if harbouring repeat lengths of ≤ 21 and CAG long (CAG(L)) if CAG >21. GGN was considered short (GGN(S)) or long (GGN(L)) if GGN ≤ 23 or >23, respectively. No significant differences in lean body mass or fitness were observed between the CAG(S) and CAG(L) groups, or between GGN(S) and GGN(L) groups, but a trend for a correlation was found for the GGN repeat and lean mass of the extremities (r=-0.11, p=0.06). In summary, the lengths of CAG and GGN repeat of the AR gene do not appear to influence lean mass or fitness in young men.

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

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

Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism

Introduction: Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. Aim: To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). Methods: Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. Main outcome measures: International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. Results: TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Δ-) of sexual function domains, except for Δ-OS. Conversely, Δ-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Δ-IS and Δ-OS. Δ-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Δ-EF, Δ-SD, Δ-IS, and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated with Δ-EF, Δ-OF, Δ-SD, and Δ-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Δ-EF and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated only with Δ-EF. Conclusions: Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH.

Association of androgen receptor CAG repeat polymorphism with VO₂max response to hypoxic training in North China Han men

The purposes of this study were to investigate the distribution characteristics of CAG repeat polymorphism in exon 1 of androgen receptor gene and the association of CAG polymorphism with VO₂max response to hypoxic training in North China Han men. Sixty-five healthy young men completed a 30-day HiHiLo training (living high, exercise high and training low) in a simulated normobaric hypoxic environment. All subjects slept in 14.3-14.8% O₂ concentration, and participated in hypoxic training three times a week in 15.4% O₂ concentration. VO₂max (peak oxygen consumption) and body weight were measured before and after hypoxic training. A total of 15 repeat alleles were observed by CAG genotype analyze, in which (CAG)22 was most common. When using 21 and 22 alleles, respectively, as cut-off points, we found that the baseline body weight of two shorter genotype groups was significantly lower than that of longer ones, and that the ΔVO₂max and ΔrVO₂max (Δrelative value of VO₂max) of two shorter genotype groups were significantly higher than those of longer ones after hypoxic training. These findings indicated that AR CAG repeat polymorphism was associated with the exercise performance after simulated normobaric hypoxic HiHiLo training in North China Han men, and that the shorter genotypes had a better individual response to hypoxic training.

The androgen receptor CAG repeat polymorphism

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

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

Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis

Context: Many studies have investigated the association between male infertility and trinucleotide repeat polymorphisms in the androgen receptor (AR) gene, but no comprehensive meta-analysis of all published studies has been conducted. Objective: Our goals were to summarize published data on associations between AR CAG and GGC repeat lengths and male infertility and investigate sources of variation between study results. Data sources: We searched for reports published before October 2006 using Medline, PubMed, and Web of Science. Study selection: All selected studies included the following: a case group with infertility as measured by semen parameters, a control group of known or presumed fertile men, and measurement of CAG and/or GGC repeat lengths among cases and controls. Thirty-nine reports were selected based on these criteria, and 33 were ultimately included in the meta-analysis. Data extraction: One investigator extracted data on sample size, mean and sd of trinucleotide repeat length, and study characteristics. Data synthesis: Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies. Conclusions: This meta-analysis provides support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility.

Native functions of short tandem repeats

Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.

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.

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.

Sex hormone levels, genetic androgen receptor polymorphism, and anxiety in ≥50-year-old males

Introduction: While associations between somatic changes and sex hormone levels in aging men have been explored in many studies, the association of testosterone and estradiol with psychic symptoms other than depression and the role of the genetically determined CAG repeat (CAGn) polymorphism of the androgen receptor (AR) have received much less attention. Aim: The purpose of this article is to investigate the associations between general anxiety, phobic anxiety and panic with sex hormone levels and the genetic androgen receptor polymorphism in aging males. Methods: This cross-sectional study of males aged ≥50 years included 120 consecutive patients of the Department of Psychosomatics and Psychotherapy, 76 consecutive patients of the Andrology Clinic, and 100 participants from the general population; all of them completed the Brief Symptom Inventory (BSI), the Aging Males' Symptoms (AMS) Scale, and the Patient Health Questionnaire (PHQ-9). Morning blood samples were analyzed for total and free testosterone, estradiol, sex hormone-binding globulin (SHBG), and the CAGn AR polymorphism. Psychosomatic patients also underwent psychiatric assessment. Main outcome measures: Scores on the Anxiety subscales of the BSI and PHQ, Anxiety disorders according to International Classification of Diseases, 10th revision (ICD-10). Results: The two clinical samples had significantly longer CAGn of the AR and higher anxiety levels compared to the population sample. Anxiety scores were positively correlated with CAGn in psychosomatic patients and in andrological patients, in the latter also with estradiol levels, while the population sample showed no significant correlations between anxiety scores, CAGn and sex hormones. Anxiety cases according to BSI, PHQ, and ICD-10 had significantly longer CAGn of the AR when compared to the other participants, but there were no significant differences in testosterone or free testosterone levels. Conclusions: Our results indicate that genetically determined long CAGn of the AR is an independent risk factor for higher anxiety, panic and phobic anxiety levels.

Androgen receptor repeat length polymorphism associated with male-to-female transsexualism

Background: There is a likely genetic component to transsexualism, and genes involved in sex steroidogenesis are good candidates. We explored the specific hypothesis that male-to-female transsexualism is associated with gene variants responsible for undermasculinization and/or feminization. Specifically, we assessed the role of disease-associated repeat length polymorphisms in the androgen receptor (AR), estrogen receptor beta (ERbeta), and aromatase (CYP19) genes. Methods: Subject-control analysis included 112 male-to-female transsexuals and 258 non-transsexual males. Associations and interactions were investigated between CAG repeat length in the AR gene, CA repeat length in the ERbeta gene, and TTTA repeat length in the CYP19 gene and male-to-female transsexualism. Results: A significant association was identified between transsexualism and the AR allele, with transsexuals having longer AR repeat lengths than non-transsexual male control subjects (p=.04). No associations for transsexualism were evident in repeat lengths for CYP19 or ERbeta genes. Individuals were then classified as short or long for each gene polymorphism on the basis of control median polymorphism lengths in order to further elucidate possible combined effects. No interaction associations between the three genes and transsexualism were identified. Conclusions: This study provides evidence that male gender identity might be partly mediated through the androgen receptor.

Sex steroid-related genes and male-to-female transsexualism

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolescents

Objective: The number of CAG repeats within the CAG repeat polymorphism of the androgen receptor (AR) gene correlates inversely with the transactivation of the receptor. We investigated the relationship between the AR CAG repeat polymorphism and longitudinal growth, puberty and body composition from prepuberty until young adult age. Design: Observational study with repeated measurements. Subjects: Two comparable young Dutch cohorts. The first cohort consisted of 226 subjects. Measurements were performed from 13 until 36 years of age. The second cohort consisted of 244 subjects. Measurements in this cohort were performed from 8 until 14 years of age. Measurements: Associations between height, height velocity, weight, BMI, fat mass, fat-free mass and pubertal development and CAG repeat length were measured. Results: Height-standard deviation scores (SDS) were inversely associated with AR CAG repeat length in boys at young, prepubertal and early pubertal age. This association diminishes in the following years and completely disappears after the age of 16 years. No associations were found with pubertal stage or any of the other parameters for body composition. Conclusions: AR CAG repeat length is inversely associated with longitudinal height in young boys, before the onset of puberty. During puberty, these differences disappear, possibly overruled by a strongly developing hypothalamic-pituitary-gonadal axis.

[Androgen receptor polymorphism in relation to medical conditions characterized by hyper/hypoandrogenism]

An androgen receptor (AR) is a transcription factor consisting of four functional regions. The transactivation region contains a highly polymorphic area characterized by a variable number of CAG trinucleotide repeats encoding a polyglutamine tract. Several in vitro studies demonstrated a negative linear relation between the lengths of CAG repeats and relative AR transactivations. Numerous clinical studies then sought associations between the described polymorphism and clinical parameters of various medical conditions characterized by hyper/hypoandrogenism. In this article, we describe some of those interesting associations. We believe such links should be investigated in any medical condition involving androgens as a key element in its pathogenesis.

Drug repurposing candidates to treat core symptoms in autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by high heritability and clinical heterogeneity. The main core symptoms are social communication deficits. There are no medications approved for the treatment of these symptoms, and medications used to treat non-specific symptoms have serious side effects. To identify potential drugs for repurposing to effectively treat ASD core symptoms, we studied ASD risk genes within networks of protein-protein interactions of gene products. We first defined an ASD network from network-based analyses, and identified approved drugs known to interact with proteins within this network. Thereafter, we evaluated if these drugs can change ASD-associated gene expression perturbations in genes in the ASD network. This was done by analyses of drug-induced versus ASD-associated gene expression, where opposite gene expression perturbations in drug versus ASD indicate that the drug could counteract ASD-associated perturbations. Four drugs showing significant (p < 0.05) opposite gene expression perturbations in drug versus ASD were identified: Loperamide, bromocriptine, drospirenone, and progesterone. These drugs act on ASD-related biological systems, indicating that these drugs could effectively treat ASD core symptoms. Based on our bioinformatics analyses of ASD genetics, we shortlist potential drug repurposing candidates that warrant clinical translation to treat core symptoms in ASD.

Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility

The X-linked androgen receptor (AR) gene contains two polymorphic trinucleotide repeat segments that code for polyglutamine and polyglycine tracts in the N-terminal trans-activation domain of the AR protein. Changes in the lengths of these polymorphic repeat segments have been associated with increased risk of prostate cancer, an androgen-dependent tumor. Expansion of the polyglutamine tract causes a rare neuromuscular disease, spinal bulbar muscular atrophy, that is associated with low virilization, reduced sperm production, testicular atrophy, and infertility. As spermatogenesis is exquisitely androgen dependent, it is plausible that changes in these two repeat segments could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, we examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines (Gln) in their AR had more than 4-fold (95% confidence interval, 4.9-3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. Concordantly, the risk of defective spermatogenesis was halved when the polyglutamine tract was short (< or = 23 Gln). Whole cell transfection experiments using AR constructs harboring 15, 20, and 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the AR was unlikely to be due to a change in AR protein content. The data indicate a direct relation between length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased functional competence of AR with longer glutamine tracts.

Androgen receptor gene CAG repeat polymorphism independently influences recovery of male sexual function after testosterone replacement therapy in postsurgical hypogonadotropic hypogonadism

Introduction: Few and contradictory studies have evaluated the possible influence of androgen receptor (AR) gene CAG repeat polymorphism on male sexual function. Aim: In this study we evaluated the role of AR gene CAG repeat polymorphism in the recovery of sexual function after testosterone replacement therapy (TRT) in men affected by postsurgical hypogonadotropic hypogonadism, a condition which is often associated with hypopituitarism and in which the sexual benefits of TRT must be distinguished from those of pituitary-function replacement therapies. Methods: Fifteen men affected by postsurgical hypogonadotropic hypogonadism were retrospectively assessed before and after TRT. Main outcome measures: Main outcome measures included sexual parameters as assessed by the International Index of Erectile Function questionnaire, levels of pituitary dependent hormones (total testosterone, free T3, free T4, cortisol, insulin-like growth factor-1 [IGF-1], prolactin), and results of genetic analysis (AR gene CAG repeat number). Results: Plasma concentrations of free T3, free T4, cortisol, and prolactin did not vary significantly between the two phases, while testosterone and IGF-1 increased significantly after TRT. A significant improvement in all sexual parameters studied was found. The number of CAG triplets was negatively and significantly correlated with changes in all the sexual parameters, while opposite correlations were found between changes in sexual parameters and changes in testosterone levels; no correlation of change in IGF1 with change in sexual parameters was reported. On multiple linear regression analysis, after correction for changes in testosterone, nearly all the associations between the number of CAG triplets and changes in sexual parameters were confirmed. Conclusions: Shorter length AR gene CAG repeat number is associated with the recovery of sexual function after TRT in postsurgical male hypogonadotropic hypogonadism, independently of the effects of concomitant pituitary-replacement therapies.

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

Introduction and aim: 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. Methods: 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). Results: 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. Conclusions: Our data suggest that, in post-surgical male hypogonadotropic hypogonadism, shorter AR CAG tract is independently associated with greater TRT-induced improvement of BMD.

The role of vitamin D in male fertility: A focus on the testis

In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non-genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function.

The Role of Dietary Nutrients in Male Infertility: A Review

Male infertility is the main health issue with economic, psychological, and medical attributions. Moreover, it is characterized by an inability to produce a sufficient amount of sperm for the fertilization of an oocyte. Dietary nutrients (DN) have a great effect on male reproductive potential. Observations have indicated that adding DN may protect or treat male infertility. The scope of this criticism is to scrutinize the DN, such as omega-3 fatty acids, vitamins, minerals and other phytochemicals, in enhancing the semen attributes, sperm bioenergetics and sperm functionality in male infertility. It seems that diets rich in omega-3 fatty acids affect sperm quality and maintain the sperm membrane and mitochondria stability. An administration of phytochemicals caused an escalation in sperm mitochondrial function and a decrease in oxidative damage. Furthermore, sundry dietary natural phytochemicals differentially affect (negatively or positively) sperm motility, semen quality, and mitochondrial function, dependent on their levels. Vitamins and trace elements are also nutritional modulators in reducing oxidative stress, thereby enhancing sperm quality, which is accurately connected with sperm mitochondrial function. Also, we described the different types of DN as mitochondrial enhancer for sperm functionality and health. We believe that understanding the DN supports sperm mitochondria and epigenetic modulators that may be responsible for sperm quality and health, and will lead to more embattled and efficient therapeutics for male infertility.

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.

Possible role of androgen receptor gene in therapeutic response of infertile men with hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism (HH) is defined as a dysfunction of hypothalamic-pituitary-gonadal axis, which causes impairments in gametogenesis, pubertal maturation, and/or secretion of the gonadal sex hormones. Human chronic gonadotropin (hCG) stimulates the Leydig cells of the testis to secrete testosterone, which is essential for spermatogenesis. Testosterone replacement therapy is one of the possible options to manage HH treatment. Given the fact that testosterone functions are mediated via androgen receptor (AR), the aim of the present study was to evaluate whether the CAG/GGN triple repeat expansion in AR gene can modulate the response to hCG and testosterone treatment in HH men. Sixty-two men who diagnosed with HH and treated with testosterone and hCG were assessed after treatment. They were classified into two groups, 31 subjects with a positive and 31 subjects with a negative response to replacement therapy within 12-18 months. Androgen receptor CAG and GGN repeat numbers were measured in both groups by hot start polymerase chain reaction (PCR)-sequencing technique. Subjects who reached complete spermatogenesis showed the 20 and 23 as the median numbers of AR CAG/GGN repeats, respectively. In individuals who did not respond to treatment the median length for both CAG/GGN repeats were 23. The average of CAG repeats was statistically lower in patients who had the positive response in comparison to patients who did not respond to hormone therapy (p < 0.05), but the length of GGN repeats were not statistically different between these groups of patients (p > 0.05). The number of CAG repeats are negatively and significantly associated with better hormone therapy response. Our results suggest that the length of CAG repeat polymorphism in AR gene might affect the response to treatment in men suffering from HH, whereas no relationship was found between AR gene GGN repeat polymorphism and testosterone and hCG replacement therapy response. Abbreviations: AR: androgen receptor; FSH: follicle stimulating hormone; Gn: gonadotropins; GnRH: gonadotropin-releasing hormone; hCG: human chronic gonadotropin; HH: hypogonadotropic hypogonadism; LH: luteinizing hormone; PCR: polymerase chain reaction.

Polymorphism of the androgen receptor gene is associated with male pattern baldness

The common heritable loss of scalp hair known as male pattern baldness or androgenetic alopecia affects up to 80% of males by age 80. A balding scalp is characterized by high levels of the potent androgen dihydrotestosterone and increased expression of the androgen receptor gene. To determine if the androgen receptor gene is associated with male pattern baldness, we compared allele frequencies of the androgen receptor gene polymorphisms (StuI restriction fragment length polymorphism and two triplet repeat polymorphisms) in cases with cosmetically significant baldness (54 young and 392 older men) and controls (107 older men) with no indication of baldness. The androgen receptor gene StuI restriction site was found in all but one (98.1%) of the 54 young bald men (p = 0.0005) and in 92.3% of older balding men (p = 0.000004) but in only 76.6% of nonbald men. The combination of shorter CAG and GGC triplet repeat lengths was also more prevalent in bald men (p = 0.03). The ubiquity of the androgen receptor gene StuI restriction site, and higher incidence of shorter triplet repeat haplotypes in bald men suggests that these markers are very close to a functional variant that is a necessary component of the polygenic determination of male pattern baldness. Functional mutation in or near the androgen receptor gene may explain the reported high levels of expression of this gene in the balding scalp.

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

Objectives: 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. Methods: 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. Results: 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). Conclusions: 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.

Mechanisms of disease: pharmacogenetics of testosterone therapy in hypogonadal men

A defective, mutated androgen receptor may lead to variable phenotypes of androgen insensitivity in humans. Also, the CAG repeat polymorphism in exon 1 of the androgen receptor gene modulates androgen effects; in vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues. Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in various tissues and psychological traits in healthy eugonadal men: the longer the repeat tracts, the less pronounced is the androgen effect when individuals with similar testosterone concentrations are compared. Furthermore, as effects of testosterone substitution are markedly influenced by the number of CAG repeats, the pharmacogenetic implications of this polymorphism are likely to have a significant role in future testosterone treatment of hypogonadal men. Thresholds at which testosterone treatment should be initiated, as well as androgen dosage, might be tailored according to the receptor polymorphism.

Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism

In men, testosterone (T) deficiency is associated with decreased physical performance, as defined by adverse traits in body composition, namely increased body fat content and reduced muscle mass. Physical abilities in androgen-deficient men are further attenuated by lower oxygen supply due to decreased hemoglobin concentrations and by poor glucose utilization. Dysthymia and a lack of necessary aggressiveness also contribute to deteriorate physical effectiveness. Substitution of T can improve lipid and insulin metabolism as well as growth of muscle fibers and decreasing fat depots, which consequently will result in changes of body composition. Increment of bone density will further contribute to increase physical fitness. The effects of T replacement therapy (TRT) are strongly influenced by age, training, and also pharmacogenetics: the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene modulates androgen effects. In vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues. Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men as well as efficacy of TRT. Thresholds at which T treatment should be initiated, as well as androgen dosage, could be tailored according to this polymorphism.

Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men

Context: A reliable form of androgen substitution therapy regarding kinetics, tolerance, and restoration of androgenicity is paramount in hypogonadal men. Intramuscular injection of the long-acting ester testosterone undecanoate (TU) offers a new modality. Objective: The objective of the study was to assess the safety of TU regarding metabolic and pharmacogenetic confounders. Design: This was a longitudinal one-arm open observation trial. A minimum of five individual assessments was a prerequisite. Putative modulators of safety parameters entering regression models were nadir and/or delta total testosterone concentrations, body mass index, androgen receptor (AR) gene CAG repeat length, and age. Setting: The study was conducted at an andrological outpatient clinic. Patients: Patients included 66 hypogonadal men (mean age 38 +/- 9.9 yr). Main outcome measures: A total of 515 data time points each related to prostate, erythropoiesis, lipoproteins, and circulation during 118 treatment-years with 1000 mg TU at 10- to 14-wk intervals. Results: Testosterone substitution resulted in significant decrements of serum levels of low-density lipoprotein-cholesterol, resting diastolic and systolic blood pressure, and heart rate. Erythropoiesis was stimulated and concentrations of high-density lipoproteincholesterol increased. Parameters remained stable after four injections. No adverse effects regarding the prostate were observed. Significantly increased hematocrit greater than 50% was predicted by enhanced androgen action (shorter AR CAG repeats per higher testosterone levels). However, insufficient androgen action (longer AR CAG repeats per lower testosterone levels) caused pathological safety parameters (high blood pressure, adverse lipid profiles). In addition, a body mass index 30 kg/m(2) or greater represents a clinically relevant factor for the occurrence of all pathological safety parameters. Risk calculations for obese patients and nonlinear pharmacogenetic models to tailor androgen substitution are presented. Conclusions: Testosterone substitution with im TU is generally well tolerated. Modifications of androgen action are due to both AR CAG repeats and testosterone levels. Adverse observations are mostly seen in obese patients.

Pharmacogenetics of testosterone replacement therapy

Variable phenotypes of androgen insensitivity exist in humans, mainly owing to defective, mutated androgen receptors. A more subtle modulation of androgen effects is related to the CAG repeat polymorphism ([CAG]n) in exon 1 of the androgen receptor gene, in vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplets. As a clinical entity, the CAG repeat polymorphism can relate to variations of androgenicity in (apparently) eugonadal men in various tissues and psychological traits, the longer the (CAG)n, the less prominent the androgen effect when individuals with similar testosterone concentrations are compared. A strictly defined threshold to hypogonadism is likely to be replaced by a continuum spanned by genetics as well as symptom specificity. In addition, effects of externally applied testosterone can be markedly influenced by the (CAG)n and respective pharmacogenetic implications are likely influence indications as well as modalities of testosterone treatment of hypogonadal men.

Polymorphisms in androgen and estrogen receptor genes: effects on male aging

Besides lifestyle and environmental factors, the life-long exposure to the endocrine milieu of gonadal steroids is a determining factor to gender specific features of aging. In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, cross-sectional and longitudinal population studies demonstrate that the hormones with anabolic actions (e.g. testosterone [T], growth hormone, insulin-like growth factor [IGF]-1, dehydroepiandrosterone) do decrease progressively with aging in healthy men, and chronic systemic illnesses accelerate this process. In addition, estrogen has recently been established to be essential for normal physiology of the male. The slow progressive decline of the hypothalamic-pituitary-gonadal (HPG) function is thought to be responsible for many common signs and symptoms of aging men, such as general weakness, sexual dysfunction, and increased fat mass. There is a large inter-individual variation in sex hormone levels cross-sectionally within given age groups as well as longitudinally with aging. A contributing factor to this variability are the numerous functionally significant polymorphisms that have been detected in the receptors for androgen and estrogen. In this review, we summarize the recent information on some common polymorphisms in androgen and estrogen receptor genes and their effect on gender specific and aging-related symptoms and diseases of men.

Synergistic effect of follicle-stimulating hormone receptor and androgen receptor gene variants on semen quality

Follicle-stimulating hormone (FSH), interacting with its receptor (FSHR), participates in the production of spermatozoa and androgens. Androgens exert their effects on male sex determination, development and sperm production by binding to androgen receptor (AR). In the present study, we sought to explore the potential synergistic effects of FSHR and AR gene variants on sperm quality. 200 oligozoospermic and 250 normozoospermic men were examined. DNA was extracted from spermatozoa, and the FSHR 307 (T/A), FSHR 680 (N/S) and AR (CAG)n polymorphisms were genotyped. Their parallel analysis revealed six combined genotypes. A gradual reduction of sperm motility, from long AR allele-Thr307Thr/Asn680Asn carriers to long AR allele-Ala307Ala/Ser680Ser carriers and from short AR allele-Thr307Thr/Asn680Asn carriers to short AR allele-Ala307Ala/Ser680Ser carriers was revealed in normozoospermic men (P < 0.001). Similar associations were observed in oligozoospermic men (P < 0.001). In our series, the synergism of the long AR alleles with the FSHRThr307/Asn680 allelic variant was associated with increased sperm motility, while the synergism of the short AR alleles with the FSHRAla307/Ser680 allelic variant was associated with decreased motility, supporting the significance of these genes in semen quality.

Synergistic effect of androgen receptor (CAG repeat length) and endothelial nitric oxide synthase (Glu298Asp variant) gene polymorphisms on seminal parameters in men with idiopathic oligoasthenozoospermia

Endothelial nitric oxide synthase (eNOS) T-786C, 4a4b, and G894T polymorphisms and male infertility: study for idiopathic asthenozoospermia and meta-analysis

Recent studies on the eNOS gene and male infertility show that expression of eNOS regulates normal spermatogenesis in the testis, and the eNOS gene variants (T-786C, 4a4b, and G894T) are potentially involved in impairment of spermatogenesis and sperm function. Thus, we conducted this association and meta-analysis study to further validate whether variants of those three loci affected the risk of idiopathic asthenozoospermia (AZS) and male infertility. Approximately 340 Chinese idiopathic AZS patients and 342 healthy men were included for this case-control study, genotyped by gel electrophoresis analysis or direct sequencing of PCR products. The eNOS mRNA isolated from the semen of patients was further examined by quantitative real-time PCR. Also, a meta-analysis of association between eNOS gene polymorphisms and male infertility was performed. A significant association was identified on allelic level between 4a4b variant and AZS in our study (chi-squared = 7.53, corrected P = 0.018, odds ratio (OR) = 1.808), while there were no significant difference of T-786C and G894T for asthenozoospermia in both genotype and allele distributions. In addition, expression of eNOS was up-regulated in patients compared with controls (about 2.4-fold, P < 0.001). Furthermore, the results of the meta-analysis support the conclusion that the T-786C and 4a4b loci were associated with male infertility in both Asian and Caucasian populations. Our study provides genetic evidence for the eNOS gene being a risk factor for idiopathic AZS and male infertility. Considering genetic differences among populations and complex pathogenesis of male infertility, more validating studies using independent samples are suggested in the future.

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.

Androgen receptor gene microsatellite polymorphism is associated with muscle mass and strength in bodybuilders and power athlete status

Background: The androgen receptor (AR) gene contains a polymorphic trinucleotide (CAG) microsatellite repeat sequence (short or long alleles) that has been associated with fat-free mass in untrained men, which needs to be replicated in athletic cohorts. Aim: The purpose of this study was to explore the AR (CAG)n polymorphism in trained individuals. Subjects and methods: A total of 61 professional bodybuilders (40 males, 21 females), 73 elite male sprinters and weightlifters and 186 male controls were enrolled in this study. The influence of the AR (CAG)n polymorphism on muscle mass and strength was assessed in bodybuilders, while the frequencies of AR (CAG)n alleles were compared between power athletes and non-athletes. Results: The polymorphism was associated with anthropometric and strength measurements in bodybuilders of both genders. Those with ≥21 CAG repeats (i.e. carriers of long alleles) exhibited greater (p < 0.05) body mass index, absolute muscle mass, arm/thigh circumference and upper/lower limb strength compared to those with <21 CAG repeats. Furthermore, carriers of ≥21 CAG repeats were more frequent among power athletes compared to controls (p = 0.0076). Conclusions: Long alleles of the AR (CAG)n polymorphism were associated with greater muscle mass and strength in bodybuilders, and power athlete status.

Polygenic Profile of Elite Strength Athletes

Moreland, E, Borisov, OV, Semenova, EA, Larin, AK, Andryushchenko, ON, Andryushchenko, LB, Generozov, EV, Williams, AG, and Ahmetov, II. Polygenic profile of elite strength athletes. J Strength Cond Res 36(9): 2509-2514, 2022-Strength is a heritable trait with unknown polygenic nature. So far, more than 200 DNA polymorphisms associated with strength/power phenotypes have been identified majorly involving nonathletic populations. The aim of the present study was to investigate individually and in combination the association of 217 DNA polymorphisms previously identified as markers for strength/power phenotypes with elite strength athlete status. A case-control study involved 83 Russian professional strength athletes (53 weightlifters, 30 powerlifters), 209 Russian and 503 European controls. Genotyping was conducted using micro-array analysis. Twenty-eight DNA polymorphisms (located near or in ABHD17C , ACTG1 , ADCY3 , ADPGK , ANGPT2 , ARPP21 , BCDIN3D , CRTAC1 , DHODH , GBE1 , IGF1 , IL6 , ITPR1 , KIF1B , LRPPRC , MMS22L , MTHFR , NPIPB6 , PHACTR1 , PLEKHB1 , PPARG , PPARGC1A , R3HDM1 , RASGRF1 , RMC1 , SLC39A8 , TFAP2D , ZKSCAN5 genes) were identified to have an association with strength athlete status. Next, to assess the combined impact of all 28 DNA polymorphisms, all athletes were classified according to the number of "strength" alleles they possessed. All highly elite strength athletes were carriers of at least 22 (up to 34) "strength" alleles, whereas 27.8% of Russian controls had less than 22 "strength" alleles ( p < 0.0001). The proportion of subjects with a high (≥26) number of "strength" alleles was significantly greater in highly elite strength athletes (84.8%) compared with less successful strength athletes (64.9%; odd ratio [OR] = 3.0, p = 0.042), Russian (26.3%; OR = 15.6, p < 0.0001) or European (37.8%; OR = 6.4, p < 0.0001) controls. This is the first study to demonstrate that the likelihood of becoming an elite strength athlete depends on the carriage of a high number of strength-related alleles.

Association of Elite Sports Status with Gene Variants of Peroxisome Proliferator Activated Receptors and Their Transcriptional Coactivator

Background: Although the scientific literature regarding sports genomics has grown during the last decade, some genes, such as peroxisome proliferator activated receptors (PPARs), have not been fully described in terms of their role in achieving extraordinary sports performance. Therefore, the purpose of this systematic review was to determine which elite sports performance constraints are positively influenced by PPARs and their coactivators. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used, with a combination of PPAR and sports keywords. Results: In total, 27 studies that referred to PPARs in elite athletes were included, where the Ala allele in PPARG rs1801282 was associated with strength and power elite athlete status in comparison to subelite athlete status. The C allele in PPARA rs4253778 was associated with soccer, and the G allele PPARA rs4253778 was associated with endurance elite athlete status. Other elite status endurance alleles were the Gly allele in PPARGC1A rs8192678 and the C allele PPARD rs2016520. Conclusions: PPARs can be used for estimating the potential to achieve elite status in human physical performance in strength and power, team, and aerobic sports disciplines. Carrying specific PPAR alleles can provide a partial benefit to achieving elite sports status, but does not preclude achieving elite status if they are absent.

Genomic predictors of testosterone levels are associated with muscle fiber size and strength

Purpose: Circulating testosterone levels are a heritable trait with anabolic properties in various tissues, including skeletal muscle. So far, hundreds of single nucleotide polymorphisms (SNPs) associated with testosterone levels have been identified in nonathletic populations. The aim of the present study was to test the association of 822 testosterone-increasing SNPs with muscle-related traits (muscle fiber size, fat-free mass and handgrip strength) and to validate the identified SNPs in independent cohorts of strength and power athletes. Methods: One hundred and forty-eight physically active individuals (47 females, 101 males) were assessed for cross-sectional area (CSA) of fast-twitch muscle fibers. Significant SNPs were further assessed for fat-free mass and handgrip strength in > 354,000 participants from the UK Biobank cohort. The validation cohorts included Russian elite athletes. Results: From an initial panel of 822 SNPs, we identified five testosterone-increasing alleles (DOCK3 rs77031559 G, ESR1 rs190930099 G, GLIS3 rs34706136 TG, GRAMD1B rs850294 T, TRAIP rs62260729 C) nominally associated (P < 0.05) with CSA of fast-twitch muscle fibers, fat-free mass and handgrip strength. Based on these five SNPs, the number of testosterone-increasing alleles was positively associated with testosterone levels in male athletes (P = 0.048) and greater strength performance in weightlifters (P = 0.017). Moreover, the proportion of participants with ≥ 2 testosterone-increasing alleles was higher in power athletes compared to controls (68.9 vs. 55.6%; P = 0.012). Conclusion: Testosterone-related SNPs are associated with muscle fiber size, fat-free mass and strength, which combined can partially contribute to a greater predisposition to strength/power sports.

The Associations of Androgen-Related Genes CYP21A2 and CYP19A1 with Severe Acne Vulgaris in Patients from Southwest China

Objective: Androgens acting through the androgen receptor play a crucial role in the pathogenesis of acne. This study aimed to identify whether two key genes (CYP21A2 and CYP19A1) involved in the synthesis and metabolism of androgens were associated with Pillsbury III-IV severe acne vulgaris. Methods: We carried out a standard questionnaire survey about acne and enlisted 600 Pillsbury III-IV severe acne vulgaris patients and 652 healthy controls of Han Chinese descent from Yunnan, China in the study. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot assay and analyzed for association with severe acne. Results: There was no significant difference in gender between the two groups (P = 0.085), and the age of the acne case group was significantly lower than that of the control group (P < 0.001). Our results revealed that only two SNPs, rs6474 (p.Arg102Lys) (P = 0.001) and rs6465 (P = 0.025) of the CYP21A2 gene were significantly associated with severe acne among the Han Chinese. When subjects were divided into males and females, significant associations were observed only in male patients with severe acne vulgaris for four variants: CYP21A2 rs6474 (p.Arg102Lys) (P = 0.002); CYP21A2 rs6465 (P = 0.012); CYP19A1 rs8023263 (P = 0.037); and CYP19A1 rs2470152 (P = 0.007). Haplotype analyses showed that the distribution of CYP21A2 haplotypes was significantly associated with male patients, while no association of CYP19A1 haplotypes was observed. The structure of the human CYP21A2 consists of two substrate binding sites and one substrate access channel. Conclusion: This study shed a light on a potentially important effect of CYP21A2 and CYP19A1 genes in severe acne vulgaris in the Han Chinese, especially for male patients. Future studies using independently verified datasets from a broader geographical spectrum will be valuable in identifying the causal and functional variants responsible for severe acne vulgaris within the CYP19A1 and CYP21A2 genes.

Genetic Variants Associated with Acne Vulgaris

Acne vulgaris (AV) ranks among the common chronic inflammatory disorders that impact the sebaceous components of hair follicles. Acne vulgaris is characterised by cardinal manifestations such as the presence of pimples, nodules, pustules, and cysts, which have the potential to lead to the development of acne scarring and pigmentation. The phenomenon is influenced by polygenic inheritance or can be ascribed to the interplay between multiple genes and environmental factors. In recent years, some researchers have found that some genes (such as IL, TNF, RETN, CYP family, MMPs and TIMPs genes et al) are associated with acne vulgaris and may affect the progression and prognosis of the disease. The number of reviews addressing acne-associated genetic variants, however, is limited. In that case, we have compiled a list of prevalent genes associated with acne in recent times. This helps us understand acne's genetic basis and lets us step in early for people prone to severe acne, lowering the chance of acne scars.

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