Variation in CAG repeat length of the androgen receptor gene predicts variables associated with intrasexual competitiveness in human males

An expanding body of research suggests that circulating androgens regulate the allocation of energy between mating and survival effort in human males, with higher androgen levels promoting greater investment in mating effort. Because variations in the number of CAG codon repeats in the human androgen receptor (AR) gene appear to modulate the phenotypic effects of androgens - with shorter repeat lengths associated with greater androgenic effects per unit androgen - polymorphisms in this gene may predict trait-like individual differences in the degree to which men are calibrated toward greater mating effort. Consistent with this, men in the present study with shorter CAG repeat lengths exhibited greater upper body strength and scored higher on self-report measures of dominance and prestige, all of which are argued to be indices of mating effort. Repeat length failed to predict sociosexual orientation (i.e. pursuit of short-term mating relationships), however, suggesting that the traits correlated with this polymorphism may be primarily associated with intrasexual competitiveness in the service of long-term mating effort. None of these measures of mating effort was related to baseline testosterone concentrations (either as main effects or as interactions with CAG repeat length), implying that long-term androgen exposure associated with AR gene polymorphisms may account for more variance in some androgen-dependent traits than does current testosterone concentration. These findings provide further evidence for the importance of the CAG repeat polymorphism in the AR gene in explaining a broad range of individual differences in human males.     

Androgen receptor gene sequence and basal cortisol concentrations predict men's hormonal responses to potential mates

Exposure to potential mates triggers rapid elevations of testosterone and glucocorticoid concentrations in males of many non-human species, and preliminary studies support similar effects in human males. The human studies have all reported large individual differences in these responses, however, and the present study tested whether specific biological variables may help explain these differences. Replicating past research, the present study found that men''s salivary testosterone and cortisol concentrations increased after a brief conversation with a young woman, but did not change (or slightly decreased) after a conversation with a young man. In addition, smaller numbers of CAG repeats in men''s androgen receptor gene, and lower baseline cortisol concentrations, each predicted larger testosterone responses to the interactions with women. The CAG repeat finding demonstrates that a specific genetic polymorphism predicts physiological responses to social interactions that may in turn have important downstream consequences on men''s mating behaviour. The effects of cortisol are consistent with past demonstrations of glucocorticoid inhibition of testosterone production and show that such inhibition also affects testosterone responses to social stimuli. In sum, the present study both confirms men''s hormonal reactions to potential mates and identifies novel biological variables that predict individual differences in these responses.     

2D:4D ratios in the first 2 years of life: Stability and relation to testosterone exposure and sensitivity

The relative lengths of the 2nd and 4th digits (2D:4D) may provide an easily measurable and stable anthropometric index of prenatal androgen exposure, but no study has examined the development of 2D:4D in infancy and the potential impact of neonatal testosterone levels. We collected 2D:4D ratios from 364 children between 0 and 2 years of age. Saliva samples were collected from 236 of these children 3 months after birth and analyzed for testosterone. In addition, 259 children provided DNA samples which were genotyped for the CAG repeat polymorphism in the androgen receptor. There was substantial variability across age in 2D:4D. Sex differences were small compared to adults and did not consistently reach statistical significance. This suggests that 2D:4D may not function well as a proxy measure of prenatal testosterone exposure in infancy. In addition, the interaction of salivary T and CAG repeats predicted right hand digit ratio at 12 months and left hand digit ratio at 12 months and 24 months in males. The interaction of salivary testosterone and CAG repeat length also predicted change in left hand 2D:4D from 2 weeks to 12 months in males. This suggests that 2D:4D in adults may reflect, in part, neonatal testosterone exposure. No significant relationships were observed within females. No significant relationships were observed when salivary testosterone and CAG repeats were examined independent of each other. Results have important implications for the design and interpretation of studies which use 2D:4D as a proxy measure of prenatal testosterone exposure.     

Serum Testosterone Levels and Androgen Receptor CAG Polymorphism Correlate with Hepatitis B Virus (HBV)-Related Acute Liver Failure in Male HBV Carriers

Background

Augmentation of androgen/androgen receptor (AR) pathway may influence chronic hepatitis B (CHB) more likely in males. AR activity is modulated by a polymorphic CAG repeat sequence in AR exon 1. This study aimed to investigate the relationship between serum testosterone levels, CAG repeat numbers and hepatitis B virus (HBV)-related acute liver failure (ALF).

Methods

Three hundred and seventy eight male CHB patients with ALF and 441 asymptomatic HBV carriers (AsCs) were recruited. AR CAG repeats numbers were analyzed. The serum testosterone levels of AsCs, ALFs and patients with hepatitis B flare groups, and sequential serum samples, were assessed quantitatively.

Results

The median CAG repeat (M-CAG) frequency was significantly higher in ALF patients than AsCs (P<0.001). Patients with M-CAG alleles (P<0.001, OR 3.0, 95% CI 2.1–4.2) had the highest risk for ALF. Serum testosterone levels were significantly higher (P<0.001) at hepatitis flare point (8.2±3.0 ng/mL) than inactive phase (6.4±2.0 ng/mL). CHB (8.30±2.71 ng/mL, P = 7.6×10⁻⁶) and ALF group (2.61±1.83 ng/mL, P = 1.7×10⁻¹⁷) had significantly different levels of testosterone in comparison with AsCs group (6.56±2.36 ng/mL). The serum testosterone levels sharply decreased from hepatitis flare phase to liver failure phase, and tended to be normal at the recovery phase. Male AsCs with M-CAG alleles had significantly lower serum testosterone levels (P<0.05).

Conclusions

There was a serum testosterone fluctuation during hepatitis B flare and HBV-related ALF, and the median CAG repeats in AR gene exon 1 were associated with lower serum testosterone levels in asymptomatic HBV carriers and an increased susceptibility to HBV-related ALF.     

Impossible “Choices”: The Inherent Harms of Regulating Women’s Testosterone in Sport

In April 2018, the International Association of Athletics Federations (IAAF) released new regulations placing a ceiling on women athletes’ natural testosterone levels to “ensure fair and meaningful competition.” The regulations revise previous ones with the same intent. They require women with higher natural levels of testosterone and androgen sensitivity who compete in a set of “restricted” events to lower their testosterone levels to below a designated threshold. If they do not lower their testosterone, women may compete in the male category, in an intersex category, at the national level, or in unrestricted events. Women may also challenge the regulation, whether or not they have lowered their testosterone, or quit sport. Irrespective of IAAF’s stated aims, the options forced by the new regulations are impossible choices. They violate dignity, threaten privacy, and mete out both suspicion and judgement on the sex and gender identity of the athletes regulated.     

The CAG repeat polymorphism of the androgen receptor gene and breast cancer

Background

Genetic variants in hormone receptor genes may be crucial predisposing factors for breast cancer, and microsatellites in the androgen receptor gene (AR) have been suggested to play a role. The aim of the study was to determine the association between the length of the CAG repeats in the AR gene and the development of breast cancer. Methodology: In total, 75 breast cancer cases and 50 healthy controls were analyzed for CAG repeats in the AR gene by polymerase chain reaction and the GeneScan/Genotyping technique.

Results

CAG repeat genotypes and alleles distribution were found to be significantly different between breast cancer patients and controls (P < 0.05). While the presence of CAG repeats shorter than 22 (classified as short, S) increases the risk of breast cancer, the risk is reduced by the presence of CAG repeats longer than 22. In the group of patients with breast cancer, a high tumor stage was found to have a significant association with genotype S/S of CAG repeats in the AR gene.

Conclusion

Our results suggest that the length of CAG repeats in the androgen receptor gene is associated with the risk of developing breast cancer.     

The effects of competition and implicit power motive on men's testosterone,emotion recognition,and aggression

A contribution to a special issue on Hormones and Human Competition.We investigated the effects of competition on men's testosterone levels and assessed whether androgen reactivity was associated with subsequent emotion recognition and reactive and proactive aggression. We also explored whether personalized power (p Power) moderated these relationships. In Study 1, 84 males competed on a number tracing task and interpreted emotions from facial expressions. In Study 2, 72 males competed on the same task and were assessed on proactive and reactive aggression. In both studies, contrary to the biosocial model of status (Mazur, 1985), winners' testosterone levels decreased significantly while losers' levels increased, albeit not significantly. Personalized power moderated the effect of competition outcome on testosterone change in both studies. Using the aggregate sample, we found that the effect of decreased testosterone levels among winners (compared to losers) was significant for individuals low in p Power but not for those with medium or high p Power. Testosterone change was positively related to emotion recognition, but unrelated to either aggression subtype. The testosterone-mediated relationship between winning and losing and emotion recognition was moderated by p Power. In addition, p Power moderated the direct (i.e., non-testosterone mediated) path between competition outcome and emotion recognition and both types of aggression: high p-Power winners were more accurate at deciphering others' emotions than high p-Power losers. Finally, among high p-Power men, winners aggressed more proactively than losers, whereas losers aggressed more reactively than winners. Collectively, these studies highlight the importance of implicit power motivation in modulating hormonal, cognitive, and behavioral outcomes arising from human competition.     

A novel primer extension method to detect the number of CAG repeats in the androgen receptor gene in families with X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.     

Variability of CAG tandem repeats in exon 1 of the androgen receptor gene is not related with dog intersexuality

Numerous mutations of the human androgen receptor (AR) gene cause an intersexual phenotype, called the androgen insensitivity syndrome. The intersexual phenotype is also quite often diagnosed in dogs. The aim of this study was to conduct a comparative analysis of the entire coding sequence (eight exons) of the AR gene in healthy and four intersex dogs, as well as in three other canids (the red fox, arctic fox and Chinese raccoon dog). The coding sequence of the studied species appeared to be conserved (similarity above 97%) and polymorphism was found in exon 1 only. Altogether, 2 SNPs were identified in healthy dogs, 14 in red foxes, 16 in arctic foxes and 6 were found in Chinese raccoon dogs, respectively. Moreover, a variable number of tandem repeats (CAG and CAA), encoding an array of glutamines, was also observed in this exon. The CAA codon numbers were invariable within species, but the CAG repeats were polymorphic. The highest number of the CAG and CAA repeats was found in dogs (from 40 to 42) and the observed variability was similar in intersex and healthy dogs. In the other canids the variability fell within the following ranges: 29–37 (red fox), 37–39 (arctic fox) and 29–32 (Chinese raccoon dog). In addition, a polymorphic microsatellite marker in intron 2 was found in the dog, red fox and Chinese raccoon dog. It was concluded that the polymorphism level of the AR gene in the dog was lower than in the other canids and none of the detected polymorphisms, including variability of the CAG tandem repeats, could be related with the intersexual phenotype of the studied dogs.     

Steroid Hormone Reactivity in Fathers Watching Their Children Compete

This study examines steroid production in fathers watching their children compete, extending previous research of vicarious success or failure on men’s hormone levels. Salivary testosterone and cortisol levels were measured in 18 fathers watching their children play in a soccer tournament. Participants completed a survey about the game and provided demographic information. Fathers with higher pregame testosterone levels were more likely to report that referees were biased against their children’s teams, and pre- to postgame testosterone elevation was predicted by watching sons compete rather than daughters as well as perceptions of unfair officiating. Pregame cortisol was not associated with pregame testosterone or with perceived officiating bias, but cortisol did fluctuate synergistically with testosterone during spectator competition. Although fathers showed no consistent testosterone change in response to winning or losing, pregame testosterone may mediate steroid hormone reactivity to other aspects of their children’s competition.     

PCR片段测序和基因分型两种方法对Kennedy遗传病的诊断

X连锁脊延髓肌萎缩症（SBMA）或肯尼迪病是一种成年人发病的神经变性疾病,以肌无力与慢性、进行性肌萎缩为特征. 通过PCR片段测序和基因分型法准确检测雄激素受体（AR）基因CAG复制数目,兄弟俩（来自同一个中国家庭）被确诊为隐性遗传性SBMA. 为了得到该中国家庭SMBA家系人员AR基因的CAG复制数目,我们采用了PCR片段测序和基因分型两种方法. 在该SMBA家系中有两个已发病的成年男性、未发病的年轻男性,及女性基因携带者. 两个已发病男性患者AR基因中CAG三核苷酸串重复数目分别是48和45. 以前的研究表明特定三核苷酸串重复数目的扩增可导致人类遗传性神经障碍疾病发病。我们的研究结果完全支持这一观点,SMBA中国家系的三核苷酸CAG拷贝数目检测结果表明,AR基因CAG扩增数目与SMBA发病相关. 关键词雄性激素受体; CAG多重三核苷酸重复; 肯尼迪病; 脊延髓肌萎缩症; X连锁     

Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens

Both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced.     

Competition-related testosterone,cortisol, and perceived personal success in recreational women athletes

Thirty-five women participating in one or more intramural flag-football games provided saliva samples before, immediately after, and 10 min after competition and completed an after-competition questionnaire appraising their own performance during the game. As seen in other studies of elite athletes, these recreational athletes, on average, showed significant elevations in testosterone (T) and cortisol (C) across the competition period – the “competition effect”. In winners and losers, T levels at all time points measured were positively related to athletes' appraisals of their own individual performance. Results from this study show that the competition effect for T and C is evident in recreational women athletes and provide preliminary evidence about the relationship between cognitive appraisal and competition-related T levels.     

Polymorphisme du gène du récepteur des androgènes: recherche de mosaïques tissulaires et relation avec l'infertilité masculine

Androgens are male steroid hormones necessary for initiation and maintenance of spermatogenesis. They act via a specific receptor which belongs to the nuclear receptor superfamily. The transactivation N-terminal domain of this receptor is characterized by a CAG repeat polymorphism in the first exon of the gene coding for polyglutamines. An increased CAG repeat length is involved in Kennedy's disease, a neurodegenerative disease associated with infertility and impaired virilization. Some recent studies have shown a correlation between the number of CAG repeats and male fertility. The aim of this study was to define this correlation and to determine whether or not infertile men presented a tissue mosaicism between blood and sperm, as described in several diseases involving CAG repeats. The length of CAG repeats of blood and testicular cells was measured in 36 oligospermic or azoospermic patients and 15 controls. An inverse correlation was found between CAG repeat length and total number of ejaculated spermatozoa. However, no tissue mosaicism between blood and sperm was observed in our population.     

Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver

Background

Age at onset of Huntington''s disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.

Methodology/Principal Findings

To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington''s disease CAG knock-in mice from 2–16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.

Conclusions/Significance

Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process.     

Do group size and laying order influence maternal deposition of testosterone in smooth-billed ani eggs?

The avian egg contains maternal hormones that affect behavior, growth, morphology, and offspring survival. Evidence to date suggests that patterns of yolk androgen deposition could provide females with a means to manipulate sibling competition and, thereby, increase their fitness. We examined yolk testosterone (T) concentrations in eggs of the smooth-billed ani (Crotophaga ani) to understand patterns of androgen deposition in eggs of this plural-breeding joint-nesting cooperatively breeding species. We tested the hatching asynchrony adjustment hypothesis, which states that increases in yolk androgen levels over the laying sequence function to mitigate the disadvantage of being a later-hatched chick in species without adaptive brood reduction. We also investigated the effect of group size on yolk T deposition to test the hypothesis that females in multi-female groups could give a competitive edge to their own chicks by depositing higher T levels in their eggs. Predictions of the hatching asynchrony adjustment hypothesis were supported in both single- and multi-female groups as yolk testosterone levels increased from early- to late-laid eggs. This suggests that ani females can influence nestling competition and chick survival by within-clutch differential T allocation. Unexpectedly, we did not observe an effect of group size on yolk T deposition. Yolk testosterone concentrations may not be a mere reflection of a female's hormonal status as female plasma circulating levels of T did not vary in the same direction as yolk T levels. Results of this study therefore support the idea that females may adaptively manipulate chick behavior through hormonal deposition in eggs.     

Testosterone and intrasexual competition in men: is there any relation with digit ratio (2D:4D)?

Digit ratio 2D:4D is a sexually dimorphic characteristic and it is believed that this difference is related to high levels of prenatal testosterone and circulating testosterone in men. High levels of testosterone are also associated with traits related to competitiveness. Therefore, this study aimed to examine the relation between intrasexual competition and 2D:4D in men. One hundred thirteen college men answered a questionnaire to measure their scores of intrasexual competition and donated a saliva sample to measure their testosterone levels; finally, the finger length from both hands was measured. It was found a positive correlation between testosterone levels and intrasexual competition scores, and a negative correlation between testosterone levels and left 2D:4D. Finally, we did not find a significant association between digit ratios 2D:4D and intrasexual competition scores. Our study shows that men with higher testosterone levels also have higher intrasexual competition scores and lower values of left digit ratio 2D:4D. Further studies will have to take into account fluctuations in testosterone over the time to observe if the relation between competitiveness scores and digit ratios 2D:4D becomes significant.