Excluded and ashamed: Shame proneness interacts with social exclusion and testosterone reactivity to predict behavioral aggression.

Exclusion from social relationships is a painful experience that may threaten an individual's status and dominance. The steroid hormone testosterone, which fluctuates rapidly in response to such threats, may be implicated in subsequent behavioral action (e.g., aggressive or prosocial responses) that aims to protect or enhance one's status after exclusion. Past research, however, indicates that the link between acute changes in testosterone and behavior depend on context-relevant individual dispositions. In the context of social exclusion, an individual's level of shame proneness-characterized by a tendency to experience shame and to react submissively-is theoretically relevant to the testosterone-induced aggression relationship but has yet to be examined empirically. Here, men (n = 167) were randomly assigned to be socially included or excluded in the virtual ball-tossing game, Cyberball, after which aggressive behavior was examined using the Point Subtraction Aggression Paradigm (PSAP). Testosterone reactivity was measured via salivary hormone samples collected pre- and post-game. Moderated multiple regression analyses were run to examine the extent to which testosterone reactivity and shame proneness moderated the effect of Cyberball condition on aggression. Results revealed a significant two-way interaction between Cyberball condition and testosterone reactivity, as well as a three-way interaction including shame proneness. For individuals low in shame proneness, exclusion was associated with higher post-cyberball aggression among those who experienced a rise in testosterone but was associated with lower post-cyberball aggression among those who experienced a decrease in testosterone. For individuals high in shame proneness, however, exclusion did not meaningfully affect aggressive responses, regardless of whether they experienced an increase or decrease in testosterone. These findings extend our understanding of the moderating roles of context and disposition on the neuroendocrinology of aggression in social interaction.

Relatively rapid effects of testosterone on men's ratings of female attractiveness depend on relationship status and the attractiveness of stimulus faces.

Attractiveness judgements influence desires to initiate and maintain romantic relationships. Testosterone also predicts relationship initiation and maintenance; such effects may be driven by the hormone's modulation of attractiveness judgements, but no studies have investigated causal (and situation-dependent) effects of the hormone on these judgements. Using a placebo-controlled cross-over design, our preregistered analyses revealed order- and relationship- dependent effects: single heterosexual men judged the women as more appealing when testosterone was administered first (and placebo second), but marginally less appealing when placebo was administered first (and testosterone second). In a more complex model incorporating the women's attractiveness (as rated by an independent set of observers), however, we show that testosterone increases the appeal of women -but this effect depends upon the men's relationship status and the women's attractiveness. In partnered men (n = 53) who tend to derogate attractive alternatives (by rating them as less appealing), testosterone countered this effect, boosting the appeal of these attractive alternatives. In single men (n = 53), conversely, testosterone increased the appeal of low-attractive women. These differential effects highlight the possibility of a newly discovered mechanism whereby testosterone promotes male sexual reproduction through different routes depending on relationship status, promoting partner up- rather than down-grading when partnered and reducing choosiness when single. Further, such effects were relatively rapid [within 85 (±5) minutes], suggesting a potential non-genomic mechanism of action.

Experimental empathy induction promotes oxytocin increases and testosterone decreases.

Oxytocin and testosterone coordinate adaptive social behaviors with stimuli in the environment. Administration of oxytocin and testosterone is associated with increased and reduced indicators of empathy, respectively, but how levels of these hormones are jointly affected by naturalistic empathy-inducing stimuli remains unclear. In this study, salivary oxytocin and testosterone levels were measured in 173 healthy adults before and after watching a video involving a gravely ill child. Participants also completed questionnaires to assess psychological variables predicted to affect oxytocin reactivity (Autism-Spectrum Quotient, Interpersonal Reactivity Index, Empathy and Systemizing Quotients). On average, there was a 14% increase in oxytocin (p = 0.003) and 4% decrease in testosterone (p = 0.001) pre- to post-video. Opposite directional changes in hormone levels occurred together, as supported by a chi-square test (p < 0.001) and a circular statistics test (p < 0.05). Considered separately, psychological traits did not predict hormone levels or changes to any appreciable degree. However, oxytocin and testosterone changes were linked with empathy relative to systemizing such that: (1) 'Empathy Bias' was associated with a large oxytocin increase but little change in testosterone, while (2) 'Systemizing Bias' and 'Balance' between empathy and systemizing were associated with a decrease in testosterone but little change in oxytocin. These findings suggest that participants were divisible into 'high oxytocin responders' (relatively empathetic) and 'high testosterone responders' (balanced or systemizing-biased). These findings support a model of joint, opposite changes in oxytocin and testosterone under experimental empathy induction, with high, somewhat predictable, diversity in individual responses.

Does testosterone impair men's cognitive empathy? Evidence from two large-scale randomized controlled trials.

The capacity to infer others' mental states (known as 'mind reading' and 'cognitive empathy') is essential for social interactions across species, and its impairment characterizes psychopathological conditions such as autism spectrum disorder and schizophrenia. Previous studies reported that testosterone administration impaired cognitive empathy in healthy humans, and that a putative biomarker of prenatal testosterone exposure (finger digit ratios) moderated the effect. However, empirical support for the relationship has relied on small sample studies with mixed evidence. We investigate the reliability and generalizability of the relationship in two large-scale double-blind placebo-controlled experiments in young men (n = 243 and n = 400), using two different testosterone administration protocols. We find no evidence that cognitive empathy is impaired by testosterone administration or associated with digit ratios. With an unprecedented combined sample size, these results counter current theories and previous high-profile reports, and demonstrate that previous investigations of this topic have been statistically underpowered.

Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age-Dependent Manner.

Androgens (testosterone and DHT) increase adult hippocampal neurogenesis by increasing survival of new neurons in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in female rats and whether the effect is age-dependent. We investigated the effects of DHT, a potent androgen, on neurogenesis in young adult and middle-aged male and female rats. Rats were gonadectomized and injected with the DNA synthesis marker bromodeoxyuridine (BrdU). The following day, rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and survival of new neurons (BrdU and BrdU/NeuN) in the hippocampus of male and female rats by using immunohistochemistry. As expected, DHT increased the number of BrdU+ cells in young males but surprisingly not in middle-aged males or in young and middle-aged females. In middle age, DHT increased the proportion of BrdU/NeuN cells, an effect driven by females. Androgen receptor expression also increased with aging in both female and male rats, which may contribute to a lack of DHT neurogenic effect in middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

Testosterone reduces the threat premium in competitive resource division.

Like other animals, humans are sensitive to facial cues of threat. Recent evidence suggests that we use this information to dynamically calibrate competitive decision-making over resources, ceding more to high-threat individuals (who appear more willing/able to retaliate) and keeping more from low-threat individuals. Little is known, however, about the biological factors that support such threat assessment and decision-making systems. In a pre-registered, double-blind, placebo-controlled, cross-over testosterone administration study ( n = 118 men), we show for the first time that testosterone reduces the effects of threat on decision-making: participants ceded more resources to high-threat (versus low-threat) individuals (replicating the 'threat premium'), but this effect was blunted by testosterone, which selectively reduced the amount of resources ceded to those highest in threat. Thus, our findings suggest that testosterone influences competitive decision-making by recalibrating the integration of threat into the decision-making process.

Using a Psychopharmacogenetic Approach To Identify the Pathways Through Which-and the People for Whom-Testosterone Promotes Aggression.

Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men ( N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone's effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone's heterogeneous effects on aggression.

Effect of exogenous testosterone on cooperation depends on personality and time pressure.

The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and-in high risk men-reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.

Testosterone and Cortisol Jointly Predict the Ambiguity Premium in an Ellsberg-Urns Experiment.

Previous literature has tried to establish whether and how steroid hormones are related to economic risk-taking. In this study, we investigate the relationship between testosterone (T) and cortisol (C) on one side and attitudes toward risk and ambiguity on the other. We asked 78 male undergraduate students to complete several tasks and provide two saliva samples. In the task "Reveal the Bag," participants expressed their beliefs on an ambiguous situation in an incentivized framework. In the task "Ellsberg Bags," we elicited from the participants through an incentive-compatible mechanism the reservation prices for a risky bet and an ambiguous bet. We used the difference between the two prices to calculate each participant's ambiguity premium. We found that participants' salivary T and C levels jointly predicted the ambiguity premium. Participants featuring comparatively lower levels of T and C showed the highest levels of ambiguity aversion. The beliefs expressed by a subset of participants in the "Reveal the Bag" task rationalize (in a revealed preference sense) their choices in the "Ellsberg Bags" task.

The Williams syndrome prosociality gene GTF2I mediates oxytocin reactivity and social anxiety in a healthy population.

The neurohormone oxytocin plays a central role in human social behaviour and cognition, and oxytocin dysregulation may contribute to psychiatric disorders. However, genetic factors influencing individual variation in the oxytocinergic system remain poorly understood. We genotyped 169 healthy adults for a functional polymorphism in GTF2I (general transcription factor II-I), a gene associated with high prosociality and reduced social anxiety in Williams syndrome, a condition reported to involve high oxytocin levels and reactivity. Participants' salivary oxytocin levels were measured before and after watching a validated empathy-inducing video. Oxytocin reactivity, defined as pre- to post-video percentage change in salivary oxytocin, varied substantially and significantly between individuals with different GTF2I genotypes, with, additionally, a trend towards an interaction between genotype and sex. Individuals with more oxytocin-reactive genotypes also reported significantly lower social anxiety. These findings suggest a model whereby GTF2I has a continuum of effects on human sociality, from the extreme social phenotypes and oxytocin dysregulation associated with gene deletion in Williams syndrome, to individual differences in oxytocin reactivity and sociality associated with common polymorphisms in healthy populations.

Comparison of clear and narrow outcomes on testosterone levels in social competition.

A contribution to a special issue on Hormones and Human Competition. Social competition is associated with marked emotional, behavioral and hormonal responses, including changes in testosterone levels. The strength and direction of these responses is often modulated by levels of other hormones (e.g. cortisol) and depends on psychological factors - classically, the objective outcome of a competition (win vs. loss) but also, hypothetically, the closeness of that outcome (e.g. decisive victory vs. close victory). We manipulated these two aspects of a social contest among male participants (N=166), to investigate how testosterone and affect fluctuated as a function of clear vs. narrow wins and clear vs. narrow losses. We found that losing a competition by a small margin (a narrow loss) was experienced as more pleasant than a clear loss. Among individuals with higher levels of basal cortisol, winning the competition by a narrow margin was associated with a decrease in testosterone levels. These findings are discussed within the framework of the status instability hypothesis and the growing literature on how situational and physiological factors modulate testosterone reactivity to social contests.

The Effects of Bisphenol A Exposure at Different Developmental Time Points in an Androgen-Sensitive Neuromuscular System in Male Rats.

The industrial plasticizer bisphenol A (BPA) is a ubiquitous endocrine disruptor to which the general human population is routinely exposed. Although BPA is well known as an estrogenic mimic, there have been some suggestions that this compound may also alter activity at the androgen receptor. To determine whether BPA does have antiandrogenic properties, we evaluated BPA effects in the spinal nucleus of the bulbocavernosus and dorsolateral nucleus, sexually dimorphic groups of motor neurons in the lumbar spinal cord that are critically dependent on androgens for survival and maintenance, as well as the monomorphic retrodorsolateral nucleus. In experiment 1, we administered varying concentrations of BPA to juvenile rats pre- and postnatally and examined both the number and size of motor neurons in adulthood. In experiment 2, different doses of BPA were given to adult rats for 28 days, after which the soma size of motor neurons were measured. Although no effect of BPA on neural survival or soma size was noted after perinatal BPA exposure, BPA exposure did result in a decrease in soma size in all motor neuron pools after chronic exposure in adulthood. These findings are discussed with regard to putative antiandrogenic effects of BPA; we argue that BPA is not antiandrogenic but is acting through nonandrogen receptor-dependent mechanisms.

Social network centrality and hormones: The interaction of testosterone and cortisol.

In this study we tested whether testosterone and cortisol interacted in predicting social network centrality within a male rugby team. Using social network analysis (SNA), three measures of centrality were investigated: popularity (i.e., the number of incoming ties a participant receives), gregariousness (i.e., the number of ties leaving from a participant and reaching out to others), and betweenness (i.e., the number of times a person lies between two other individuals). In line with the idea that testosterone and cortisol jointly regulate the emergence of social status, we found that individuals with high basal testosterone and low basal cortisol were more popular and more likely to act as connectors among other individuals (i.e., betweenness). The same hormonal profile was not predictive of gregariousness. However, in line with the small literature on the topic, we found that cortisol was inversely correlated with gregariousness. Despite the cross-sectional and correlational nature of our research design, these findings represent the first empirical evidence that testosterone and cortisol interact to predict complex measures of social hierarchy position derived from social network analyses.

Face of a fighter: Bizygomatic width as a cue of formidability.

Humans can accurately extract information about men's formidability from their faces; however, the actual facial cues that inform these judgments have not been established. Here, through three studies, we test the hypothesis that bizygomatic width (i.e. facial width-to-height ratio, fWHR) covaries with actual physical formidability (hypothesis #1) and that humans use this cue when making assessments of formidability (hypothesis #2). Our data confirm that fWHR is predictive of actual fighting ability among professional combatants (study 1). We further show that subjects' assessments of formidability covary with the target's fWHR on natural faces (study 2), computer-generated images of strong and weak faces (study 2), and experimentally manipulated computer-generated faces (study 3). These results support the hypothesis that bizygomatic width is a cue of formidability that is assessed during agonistic encounters.

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology. RESULTS: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased ß-amyloid peptide levels and decreased levels of amyloid plaques. CONCLUSIONS: This study indicates that increased O-GlcNAc can influence ß-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

Losing the battle but winning the war: uncertain outcomes reverse the usual effect of winning on testosterone.

The biosocial model of status predicts a competition effect (or winner-loser effect), whereby winning a competition should cause a rise in testosterone relative to losing. However, its applicability to women and the role of contextual factors, such as a decisive versus close match, have been overlooked. In two studies of female competition, we tested whether the winner-loser effect generalizes to dominance contests that model unstable social hierarchies, namely in close competitions wherein the winner-loser distinction is unsettled (Study 1) and in competitions in which the outcome is uncertain (Study 2). In both studies we found evidence for a reverse winner-loser effect whereby losers experienced a net increase in testosterone compared to winners. Moreover, the rise in testosterone was stronger in those competitors who reported being more surprised by the loss (Study 2). These results represent some of the first empirical evidence for the reverse effect of what is predicted by the biosocial model of status. We interpret these findings in terms of the dominance motivation that testosterone might subserve within unstable status hierarchies.

Testosterone across successive competitions: evidence for a 'winner effect' in humans?

In many species testosterone fluctuates in concert with outcome-dependent changes in social status, such that winning a competition leads to an increase in circulating testosterone (i.e., competition effect). Although this phenomenon has been well studied in humans, the cumulative endocrine impact of multiple successive competitions is poorly understood. Moreover, although changes in testosterone after a competition seem to predict immediate aggressive behavior, competitive motivation, risk-taking, and affiliation, whether this endocrine response also has long-term behavioral effects, as suggested by studies in non-human animals, has not been examined. In this study, salivary testosterone was collected from pairs of male participants engaging, on two consecutive days, in head-to-head competitions on a previously validated laboratory task. We found that testosterone reactivity on the first day, which was congruent with the competition effect (i.e., net testosterone increase in randomly assigned winners), predicted the task performance on the second day. Further, when looking at testosterone reactivity on the second day, those individuals that lost both competitions experienced the steepest decline in testosterone compared to those individuals who lost on the second day but won on the first day. Testosterone fluctuations on the second day were also analyzed considering the type of status hierarchy (stable vs. unstable) that emerged as a result of the combined outcomes of the two competitions. In accordance with the challenge hypothesis, men in unstable hierarchies (first day winners/second day losers and first day losers/second day winners) experienced an increase in testosterone compared to men in the stable hierarchies (double winners and double losers). Results are discussed within a comparative perspective, drawing parallels with the winner effect and the challenge hypothesis observed in non-human animals.

Testosterone reactivity to facial display of emotions in men and women.

Previous studies have examined testosterone's role in regulating the processing of facial displays of emotions (FDEs). However, the reciprocal process - the influence of FDEs, an evolutionarily ancient and potent class of social signals, on the secretion of testosterone - has not yet been studied. To address this gap, we examined the effects of emotional content and sex of facial stimuli in modulating endogenous testosterone fluctuations, as well as sex differences in the endocrine responses to faces. One hundred and sixty-four young healthy men and women were exposed, in a between-subjects design, to happy or angry same-sex or opposite-sex facial expressions. Results showed that in both men (n=85) and women (n=79), extended exposure to faces of the opposite sex, regardless of their apparent emotional content, was accompanied by an accumulation in salivary testosterone when compared to exposure to faces of the same sex. Furthermore, testosterone change in women exposed to angry expressions was greater than testosterone change in women exposed to happy expressions. These results add emotional facial stimuli to the collection of social signals that modulate endocrine status, and are discussed with regard to the evolutionary roles of testosterone.

Androgen insensitive male rats display increased anxiety-like behavior on the elevated plus maze.

Male rats carrying the testicular feminization mutation (Tfm-affected males) are insensitive to androgens, resulting in a female-typical peripheral phenotype despite possession of inguinal testes that are androgen secretory. Androgen-dependent neural and behavioral processes may likewise show atypical sexual differentiation. Interestingly, these mutant rats display elevated serum corticosterone, suggesting a chronic anxiety phenotype and dysregulated hypothalamic-pituitary-adrenal axis. In order to understand if elevated anxiety-like behavior is a possible mediating variable affecting the display of certain androgen-dependent behaviors, we compared the performance of Tfm-affected males to wild type males and females in the elevated plus maze (EPM). Two well-established indicators of anxiety-like behavior in the EPM were analyzed: total percentage of time spent on the open arms, and the percentage of open arm entries. We also analyzed the total number of open arm entries. Interestingly, Tfm-affected males spent less percentage of time on the open arms than both males and females, suggesting increased anxiety-like behavior. Percentage of open arm entries and the total number of arm entries was comparable between the groups, indicating that the observed decrease in the percentage of time spent on the open arms was not due to a global reduction in exploratory behavior. These data, in contrast to earlier reports, thus implicate androgen receptor-mediated functions in the expression of anxiety behaviors in male rats. Given that anxiety is widely reported as a precipitating factor in depression, studying the role of the androgen receptor in anxiety may give insights into the pathogenesis of major depressive disorder.