Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Androgens and child behavior: Color and toy preferences in children with congenital adrenal hyperplasia (CAH).

Human males and females show average gender/sex differences for certain psychological phenomena. Multiple factors may contribute to these differences, including sex chromosomes, exposure to gonadal hormones, and socialization or learning. This study investigated potential hormonal and socialization/learning influences on gender/sex differences in childhood preferences for color, specifically pink and red vs. blues, and for toys. Children (aged 4 to 11 years) with congenital adrenal hyperplasia (CAH, n = 43 girls and 37 boys), marked by elevated prenatal adrenal androgen exposure, and without CAH (n = 41 girls and 31 boys) were studied. Prior research indicates girls with CAH are masculinized for certain behaviors, such as toy choices, while boys with CAH generally do not differ from boys without CAH. In the current study, children indicated preferences for stereotyped hues of pink vs. blue as well as two control color pairs. They also indicated their preference between gender/sex-typed toys (doll vs. car) presented in black and white, in gender/sex-congruent colors (pink doll vs. blue car) and in gender/sex-incongruent colors (pink car vs. blue doll). Color findings: Control girls preferred stereotyped pink over blue more than boys or girls with CAH did; the latter two groups did not differ in their color preferences. No preference differences occurred for other color pairs. Toy findings: In black/white or gender/sex-congruent colors, boys preferred the car more than control girls or girls with CAH did, while girls with CAH preferred the car more than control girls did. In gender/sex-incongruent colors (pink car vs. blue doll), boys still preferred the car, while girls with CAH showed reduced and control girls showed increased preferences for the pink car compared to the car preferences in black/white. Results support learning theories of color preferences, perhaps also influenced by pre-existing toy preferences which may occur for other reasons, including early androgen exposure. Specifically, girls with CAH may have learned they do not enjoy stereotypical toys for girls, often colored pink, and pink coloring may subsequently diminish their preference for a car. Our results highlight the importance of gonadal hormones and learning in the development of childhood toy and color preferences.

Prenatal androgen exposure and children's gender-typed behavior and toy and playmate preferences.

We report findings from two studies investigating possible relations of prenatal androgen exposure to a broad measure of children's gender-typed behavior, as well as specifically to children's toy and playmate preferences. Study 1 investigated these outcomes for 43 girls and 38 boys, aged 4 to 11 years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) compared to similarly-aged, unaffected relatives (41 girls, 31 boys). The predicted sex differences were found for all of the outcome measures. Furthermore, girls with CAH showed increased male-typical and decreased female-typical behavior and toy and playmate preferences compared to unaffected girls. Study 2 investigated the relationship of amniotic fluid testosterone to gender-typed behavior and toy and playmate preferences in typically developing children (48 girls, 44 boys) aged 3 to 5 years. Although the predicted sex differences were found for all of the outcome measures, amniotic fluid testosterone was not a significant correlate, in the predicted direction, of any outcome measure for either sex. The results of study 1 provide additional support for an influence of prenatal androgen exposure on children's gender-typed behavior, including toy and playmate preferences. The results of study 2 do not, but amniotic fluid testosterone may be an insufficiently sensitive measure of early androgen exposure. A more sensitive and reliable measure of prenatal androgen exposure may be needed to consistently detect relations to later gender typed behavior in non-clinical populations.

Sex differences in associations between spatial ability and corpus callosum morphology.

Rotating mental representations of objects is accompanied by widespread bilateral brain activations. Thus, interhemispheric communication channels may play a relevant part when engaging in mental rotation tasks. Indeed, links between mental rotation and dimensions of the corpus callosum-the brain's main commissure system-have been reported. However, existing findings are sparse and inconsistent across studies. Here we set out to further characterize the nature of any such links, including their exact location across the corpus callosum. For this purpose, we applied an advanced image analysis approach assessing callosal thickness at 100 equidistant points in a sample of 38 healthy adults (19 men, 19 women), aged between 22 and 45 years. We detected a sex interaction, with significant structure-performance relationships in women, but not in men. Specifically, better mental rotation performance was linked to a thicker female corpus callosum within regions of the callosal splenium, posterior midbody, and anterior third. These findings may suggest sex differences in problem solving strategies where in women, more than in men, stronger interhemispheric connectivity-especially between occipitoparietal, frontal, and prefrontal regions-is associated with improved task performance. © 2018 Wiley Periodicals, Inc.

Prenatal androgen exposure and children's aggressive behavior and activity level.

Some human behaviors, including aggression and activity level, differ on average for males and females. Here we report findings from two studies investigating possible relations between prenatal androgen and children's aggression and activity level. For study 1, aggression and activity level scores for 43 girls and 38 boys, aged 4 to 11years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) were compared to those of similarly-aged, unaffected relatives (41 girls, 31 boys). Girls with CAH scored higher on aggression than unaffected girls, d=0.69, and unaffected boys scored higher on activity level than unaffected girls, d=0.50. No other group differences were significant. For study 2, the relationship of amniotic fluid testosterone to aggression and activity level was investigated in typically-developing children (48 girls, 44 boys), aged 3 to 5years. Boys scored higher than girls on aggression, d=0.41, and activity level, d=0.50. However, amniotic fluid testosterone was not a significant predictor of aggression or activity level for either sex. The results of the two studies provide some support for an influence of prenatal androgen exposure on children's aggressive behavior, but not activity level. The within-sex variation in amniotic fluid testosterone may not be sufficient to allow reliable assessment of relations to aggression or activity level.

No relationship between prenatal androgen exposure and autistic traits: convergent evidence from studies of children with congenital adrenal hyperplasia and of amniotic testosterone concentrations in typically developing children.

BACKGROUND: There is a marked male preponderance in autism spectrum conditions. The extreme male brain theory and the fetal androgen theory of autism suggest that elevated prenatal testosterone exposure is a key contributor to autistic traits. The current paper reports findings from two separate studies that test this hypothesis. METHODS: A parent-report questionnaire, the Childhood Autism Spectrum Test (CAST), was employed to measure autistic traits in both studies. The first study examined autistic traits in young children with congenital adrenal hyperplasia (CAH), a condition causing unusually high concentrations of testosterone prenatally in girls. Eighty one children with CAH (43 girls) and 72 unaffected relatives (41 girls), aged 4-11 years, were assessed. The second study examined autistic traits in relation to amniotic testosterone in 92 typically developing children (48 girls), aged 3-5 years. RESULTS: Findings from neither study supported the association between prenatal androgen (testosterone) exposure and autistic traits. Specifically, young girls with and without CAH did not differ significantly in CAST scores and amniotic testosterone concentrations were not significantly associated with CAST scores in boys, girls, or the whole sample. CONCLUSIONS: These studies do not support a relationship between prenatal testosterone exposure and autistic traits. These findings augment prior research suggesting no consistent relationship between early androgen exposure and autistic traits.

Working memory performance is reduced in children with congenital adrenal hyperplasia.

Individuals with classic congenital adrenal hyperplasia (CAH) experience impaired glucocorticoid production and are treated postnatally with glucocorticoids. Prior research with animals and other human populations indicates that glucocorticoids can influence memory, particularly working memory. We tested the hypothesis that children with CAH would show reduced working memory. Children in the United Kingdom, aged 7-11years, with classical CAH (31 girls, 26 boys) were compared to their unaffected relatives (30 girls, 20 boys) on a test of working memory, the Digit Span test. Vocabulary was also assessed to measure verbal intelligence for control purposes. Children with CAH showed reduced working memory performance compared to controls, on both components of the Digit Span test: p=.008 for Digit Span Forward, and p=.027 for Digit Span Backward, and on a composite score, p=.004. These differences were of moderate size (d=.53 to .70). Similar differences were also seen in a subset of 23 matched pairs of children with CAH and their relatives (d=.78 to .92). There were no group differences on Vocabulary. Glucocorticoid abnormality, including treatment effects, could be responsible for the reduced Digit Span performance in children with CAH. Other factors related to CAH, such as salt-wasting crises, could also be involved. Additional research is needed to identify the cause of the memory reduction, which will help to determine if more rapid diagnosis or more precise glucocorticoid treatment would help prevent memory reduction. Educational interventions might also be considered for children with CAH.

Increased Cross-Gender Identification Independent of Gender Role Behavior in Girls with Congenital Adrenal Hyperplasia: Results from a Standardized Assessment of 4- to 11-Year-Old Children.

While reports showing a link between prenatal androgen exposure and human gender role behavior are consistent and the effects are robust, associations to gender identity or cross-gender identification are less clear. The aim of the current study was to investigate potential cross-gender identification in girls exposed prenatally to high concentrations of androgens due to classical congenital adrenal hyperplasia (CAH). Assessment included two standardized measures and a short parent interview assessing frequency of behavioral features of cross-gender identification as conceptualized in Part A of the diagnostic criteria for gender identity disorder (GID) in the DSM-IV-TR. Next, because existing measures may have conflated gender role behavior with gender identity and because the distinction is potentially informative, we factor analyzed items from the measures which included both gender identity and gender role items to establish the independence of the two constructs. Participants were 43 girls and 38 boys with CAH and 41 unaffected female and 31 unaffected male relatives, aged 4- to 11-years. Girls with CAH had more cross-gender responses than female controls on all three measures of cross-gender identification as well as on a composite measure of gender identity independent of gender role behavior. Furthermore, parent report indicated that 5/39 (12.8 %) of the girls with CAH exhibited cross-gender behavior in all five behavioral domains which comprise the cross-gender identification component of GID compared to 0/105 (0.0 %) of the children in the other three groups combined. These data suggest that girls exposed to high concentrations of androgens prenatally are more likely to show cross-gender identification than girls without CAH or boys with and without CAH. Our findings suggest that prenatal androgen exposure could play a role in gender identity development in healthy children, and may be relevant to gender assignment in cases of prenatal hormone disruption, including, in particular, cases of severely virilized 46, XX CAH.

Prenatal androgen exposure and sex-typical play behaviour: A meta-analysis of classic congenital adrenal hyperplasia studies.

Thousands of non-human mammal experiments have demonstrated that early androgen exposure exerts long-lasting effects on neurobehavioural sexual differentiation. In humans, females with classic congenital adrenal hyperplasia (CAH) are exposed to unusually high concentrations of androgens prenatally, whereas prenatal concentrations of androgens in males with CAH are largely normal. The current meta-analysis included 20 independent samples and employed multi-level meta-analytic models. Consistently across all 7 male-typical and female-typical play outcomes, in the expected directions, the present study found significant and large average differences between control males and control females (gs = 0.83-2.78) as well as between females with CAH and control females (gs = 0.95-1.08), but differences between males with CAH and control males were mostly negligible and were non-significant for 6 of the 7 outcomes (gs = 0.04-0.27). These meta-analytic findings suggest that prenatal androgen exposure masculinises and defeminises play behaviour in humans. Broader implications in relation to sex chromosomes, brain development, oestrogens, socio-cognitive influences, other aspects of sex-related behavioural development, and gender nonconformity are discussed.

Emotional and behavioral adjustment in 4 to 11-year-old boys and girls with classic congenital adrenal hyperplasia and unaffected siblings.

It has been suggested that atypical hormone environments during early development may contribute to subsequent development of psychopathology. Also, it has been suggested that individuals with the autosomal recessive genetic variant, classic congenital adrenal hyperplasia (CAH), might be at increased risk of psychopathology. The present study examined emotional and behavioral adjustment in young children with CAH and their unaffected siblings in the United Kingdom. The parent-reported version of the Strengths and Difficulties Questionnaire (SDQ) was employed to assess adjustment in children aged 4 to 11 years. There were 38 boys with CAH, 43 girls with CAH, 23 unaffected brothers, and 31 unaffected sisters. No differences in emotional or behavioral problems were found between boys or girls with CAH and unaffected same-sex siblings. In addition, affected and unaffected boys in the current sample generally did not differ from boys in the general population. However, compared with girls in the general population, girls with CAH had more difficulties related to conduct problems, hyperactivity/ inattention, and prosocial behavior, and unaffected sisters had more difficulties related to peer problems, conduct problems, and prosocial behavior. These findings suggest that both girls with CAH and unaffected sisters of girls or boys with CAH may be at increased risk of developing behavioral problems. Potential influences related to the early hormone environment, familial process, and social stigma are considered.

The early postnatal period, mini-puberty, provides a window on the role of testosterone in human neurobehavioural development.

Experimental research in non-human mammals indicates that testosterone exposure during early periods of rapid brain development has enduring influences on brain and behaviour. These influences are exerted when testosterone is higher in developing males than females, and the affected characteristics are those that differ by sex. Testosterone is higher in males than in females from about weeks 8 to 24 of human gestation and then again during early infancy, and both of these periods are times of rapid brain development. Substantial evidence suggests that testosterone prenatally influences human neurobehavioral development. Emerging evidence suggests that the early postnatal period is important too. This early postnatal period could provide a window for studying testosterone interacting with experience to shape human gender development.

Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development.

Early androgen exposure and human gender development.

During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This approach has recently begun to be used, with some promising results relating testosterone during the first few months of postnatal life to later gender-typical play behavior. In replicating and extending these findings, it may be important to assess testosterone when it is maximal (months 1 to 2 postnatal) and to take advantage of the increased reliability afforded by repeated sampling.

Evaluation of military trauma system practices related to damage-control resuscitation.

BACKGROUND: The Joint Theater Trauma System (JTTS) was developed with the vision that every soldier, marine, sailor, and airman injured on the battlefield would have the optimal chance for survival and maximum potential for functional recovery. In this analysis, we hypothesized that information diffusion through the JTTS, via the dissemination of clinical practice guidelines and process improvements, would be associated with the acceptance of evidence-based practices and decreases in trauma practice variability. METHODS: The current evaluation was designed as a single time-series quasi-experimental study as a preanalysis and postanalysis relative to the implementation of clinical practice guidelines and process improvement interventions. Data captured from patients admitted to hospital-level (Level III) military treatment facilities in Iraq and Afghanistan from 2003 to 2010 were retrospectively analyzed from the Joint Theater Trauma Registry (JTTR) to determine the potential impact of process improvement initiatives on clinical practice. RESULTS: The JTTS clinical practice guidelines for massive transfusion led to increased compliance with balanced component transfusion and decreased practice variability. During the course of the evaluation period, hypothermia on presentation decreased dramatically after the publication of the hypothermia prevention and management clinical practice guideline. CONCLUSION: Developed metrics demonstrate that evidence-based quality improvement initiatives disseminated through the JTTS were associated with improved clinical practice of resuscitation following battlefield injury. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV.

Evaluation of military trauma system practices related to complications after injury.

BACKGROUND: The Joint Theater Trauma System (JTTS) was developed with the vision that every soldier, marine, sailor, and airman injured on the battlefield would have the optimal chance for survival and maximum potential for functional recovery. In this analysis, we hypothesized that injury and complication after injury surveillance information diffusion through the JTTS, via the dissemination of clinical practice guidelines and process improvements, would be associated with improved combat casualty clinical outcomes. METHODS: The current analysis was designed to profile different aspects of trauma system performance improvement, including monitoring of frequent posttraumatic complications, the assessment of an emerging complication trend, and measurement of the impact of the system interventions to identify potential practices for future performance improvement. Data captured from the Joint Theater Trauma Registry on patients admitted to military medical treatment facilities as a result of wounds incurred in Iraq and Afghanistan from 2003 to 2010 were retrospectively analyzed to determine the potential impact of complication surveillance and process improvement initiatives on clinical practice. RESULTS: Developed metrics demonstrated that the surveillance capacity and evidence-based quality improvement initiatives disseminated through the JTTS were associated with improved identification and mitigation of complications following battlefield injury. CONCLUSION: The Joint Trauma System enables evidence-based practice across the continuum of military trauma care. Concurrent data collection and performance improvement activities at the local and system level facilitate timely clinical intervention on identified trauma complications and the subsequent measurement of the effectiveness of those interventions. LEVEL OF EVIDENCE: Epidemiologic study, level III.