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Congenital Adrenal Hyperplasia (CAH) has been reported to involve structural alterations in some brain regions. However, it remains to be established whether there is also an impact on the size of the brain as a whole. Here, we compiled the largest CAH sample to date (n = 53), matched pair-wise to a control group (n = 53) on sex, age, and verbal intelligence. Using T1-weighted brain scans, we calculated intracranial volume (ICV) as well as total brain volume (TBV), which are both common estimates for brain size. The statistical analysis was performed using a general linear model assessing the effects of CAH (CAH vs. controls), sex (women vs. men), and any CAH-by-sex interaction. The outcomes were comparable for ICV and TBV, i.e., there was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex, with larger ICVs and TBVs in men than in women. Our findings contribute to an understudied field of research exploring brain anatomy in CAH. In contrast to some existing studies suggesting a smaller brain size in CAH, we did not observe such an effect. In other words, ICV and TBV in women and men with CAH did not differ significantly from those in controls. Notwithstanding, we observed the well-known sex difference in brain size (12.69% for ICV and 12.50% for TBV), with larger volumes in men than in women, which is in agreement with the existing literature. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights • First study on this topic in young children with CAH and unaffected siblings. • No differences in difficulties between children with CAH and unaffected siblings. • Boys in families with a child with CAH did not show increased difficulties. • Girls with and without CAH in these families showed increased difficulties. • Stigma or parental stress may contribute to the increased difficulties in girls. Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. • Prenatal androgen exposure linked to gender-typed play behavior in girls with CAH. • Girls with CAH showed increased preference for boys as playmates. • Children without CAH showed large sex differences in gender-typed play behavior. • Amniotic fluid testosterone did not relate to gender-typed play behavior. • Amniotic fluid testosterone may not be a reliable measure of prenatal androgen. [ABSTRACT FROM AUTHOR]

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 (g s = 0.83–2.78) as well as between females with CAH and control females (g s = 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 (g s = 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. • First meta-analysis on CAH and play behaviour, evaluating over 50 years of evidence. • Play behaviour is masculinised and defeminised in females with CAH. • Prenatal androgen exposure may exert organising effects on sex-typical play. • These effects have implications for sex-related neural and behavioural development. • A review of the wider literature shows other factors may also be important. [ABSTRACT FROM AUTHOR]

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. • Girls with congenital adrenal hyperplasia show masculinized toy & color preferences. • Girls with congenital adrenal hyperplasia dislike pink compared to control girls. • Color preferences may stem from socialization/learning secondary to toy preferences. • Gonadal hormones & learning may jointly influence childhood toy & color preferences. [ABSTRACT FROM AUTHOR]

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 7–11 years, 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. [ABSTRACT FROM AUTHOR]