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.

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.

Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys.

The masculinizing effects of prenatal androgens on human neurobehavioral development are well established. Also, the early postnatal surge of androgens in male infants, or mini-puberty, has been well documented and is known to influence physiological development, including penile growth. However, neurobehavioral effects of androgen exposure during mini-puberty are largely unknown. The main aim of the current study was to evaluate possible neurobehavioral consequences of mini-puberty by relating penile growth in the early postnatal period to subsequent behavior. Using multiple linear regression, we demonstrated that penile growth between birth and three months postnatal, concurrent with mini-puberty, significantly predicted increased masculine/decreased feminine behavior assessed using the Pre-school Activities Inventory (PSAI) in 81 healthy boys at 3 to 4years of age. When we controlled for other potential influences on masculine/feminine behavior and/or penile growth, including variance in androgen exposure prenatally and body growth postnally, the predictive value of penile growth in the early postnatal period persisted. More specifically, prenatal androgen exposure, reflected in the measurement of anogenital distance (AGD), and early postnatal androgen exposure, reflected in penile growth from birth to 3months, were significant predictors of increased masculine/decreased feminine behavior, with each accounting for unique variance. Our findings suggest that independent associations of PSAI with AGD at birth and with penile growth during mini-puberty reflect prenatal and early postnatal androgen exposures respectively. Thus, we provide a novel and readily available approach for assessing effects of early androgen exposures, as well as novel evidence that early postnatal aes human neurobehavioral development.

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.

Traits of autism spectrum disorders in adults with gender dysphoria.

The literature examining the co-occurrence of gender dysphoria (GD) and autistic traits has so far been limited to a series of small case studies and two systematic studies, one looking at autistic traits in gender dysphoric children and the other set within the context of the extreme male brain hypothesis and looking at adults. The current study examined this co-occurrence of GD and autistic traits in an adult population, to see whether this heightened prevalence persisted from childhood as well as to provide further comparison of MtF versus FtM transsexuals and homosexual versus nonhomosexual individuals. Using the Autistic Spectrum Quotient (AQ), 91 GD adults (63 male-to-female [MtF] and 28 female-to-male [FtM]) undertaking treatment at a gender clinic completed the AQ. The prevalence of autistic traits consistent with a clinical diagnosis for an autism spectrum disorder (ASD) was 5.5 % (n = 3 MtF and n = 2 FtM) compared to reports of clinical diagnoses of 0.5-2.0 % in the general population. In contrast to the single previous report in adults, there was no significant difference between MtF and FtM on AQ scores; however, all of those who scored above the clinical cut-off were classified as nonhomosexual with respect to natal sex. Results were considered in the context of emerging theories for the observed co-occurrence of GD and autistic traits.

Predictors of posttraumatic stress in parents of children diagnosed with a disorder of sex development.

The aims of the current study were twofold: (1) to assess the prevalence/severity of posttraumatic stress symptoms (PTSS) as well as cognitive and emotional responses in parents whose children were diagnosed with a disorder of sex development (DSD); and (2) to assess factors which contributed to PTSS. We hypothesized that parents would show elevated levels of PTSS and that negative cognitive and/or emotional responses would be predictive. Participants were parents of children diagnosed with a DSD. Thirty-six mothers and 11 fathers completed a measure of posttraumatic stress and reported difficulties in the domains of cognition (e.g., confusion) and emotion (e.g., grief). Using multiple regression, we determined factors contributing to parental PTSS. Reported PTSS was high: 31 % of mothers and 18 % of fathers met the threshold for caseness for Posttraumatic Stress Disorder. Regression included: child sex, parent sex, child age at diagnosis, years since diagnosis, genital ambiguity, father occupation, cognitive confusion, and emotional distress. Only cognitive confusion contributed significantly to variance in PTSS. Parents of children with DSD may experience the diagnosis as traumatic, evidenced by high rates of PTSS in the current report. Assessment of reactions to their children's diagnoses revealed that cognitive confusion, and not emotional distress, predicted PTSS. In this case, direct cognitive interventions may be applicable. Though psychological support is widely recommended, no detailed intervention has been offered. Our findings suggest that we may directly apply models successful in other areas of pediatrics, such as pediatric oncology. Future studies may assess the usefulness of such an intervention.

Androgen insensitivity syndrome.

Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

Are there parental socialization effects on the sex-typed behavior of individuals with congenital adrenal hyperplasia?

Influences of prenatal androgen exposure on human sex-typical behavior have been established largely through studies of individuals with congenital adrenal hyperplasia (CAH). However, evidence that addresses the potential confounding influence of parental socialization is limited. Parental socialization and its relationship to sex-typical toy play and spatial ability were investigated in two samples involving 137 individuals with CAH and 107 healthy controls. Females with CAH showed more boy-typical toy play and better targeting performance than control females, but did not differ in mental rotations performance. Males with CAH showed worse mental rotations performance than control males, but did not differ in sex-typical toy play or targeting. Reported parental encouragement of girl-typical toy play correlated with girl-typical toy play in all four groups. Moreover, parents reported encouraging less girl-typical, and more boy-typical, toy play in females with CAH than in control females and this reported encouragement partially mediated the relationship between CAH status and sex-typical toy play. Other evidence suggests that the reported parental encouragement of sex-atypical toy play in girls with CAH may be a response to the girls' preferences for boys' toys. Nevertheless, this encouragement could further increase boy-typical behavior in girls with CAH. In contrast to the results for toy play, we found no differential parental socialization for spatial activities and little evidence linking parental socialization to spatial ability. Overall, evidence suggests that prenatal androgen exposure and parental socialization both contribute to sex-typical toy play.

Prenatal hormones and childhood sex segregation: playmate and play style preferences in girls with congenital adrenal hyperplasia.

We investigated playmate and play style preference in children with congenital adrenal hyperplasia (CAH) (26 females, 31 males) and their unaffected siblings (26 females, 17 males) using the Playmate and Play Style Preferences Structured Interview (PPPSI). Both unaffected boys and girls preferred same-sex playmates and sex-typical play styles. In the conflict condition where children chose between a same-sex playmate engaged in an other-sex activity or an other-sex playmate engaged in a same-sex activity, boys (both CAH and unaffected brothers) almost exclusively chose playmates based on the preferred play style of the playmate as opposed to the preferred gender label of the playmate. By contrast, unaffected girls used play style and gender label about equally when choosing playmates. Girls with CAH showed a pattern similar to that of boys: their playmate selections were more masculine than unaffected girls, they preferred a boy-typical play style and, in the conflict condition, chose playmates engaged in a masculine activity. These findings suggest that prenatal androgen exposure contributes to sex differences in playmate selection observed in typically developing children and that, among boys and girls exposed to high levels of androgens prenatally, play style preferences drive sex segregation in play.

Sex differences in semantic categorization.

Sex differences in certain cognitive abilities, including aspects of semantic processing, are well established. However, there have been no reports investigating a sex difference in semantic categorization. A total of 55 men and 58 women each judged 25 exemplars of natural categories (e.g., FRUITS) and 25 of artifact categories (e.g., TOOLS) as a nonmember, partial member, or full member of the given category. Participants also rated confidence for each judgment. Women provided a greater number of vague (partial member) judgments whereas men provided more inclusive (full member) judgments of artifacts but more exclusive (nonmember) judgments of natural categories. The sex difference in vagueness was observed across domains (Cohen's d = .56). Confidence predicted categorization among both men and women, such that more confident participants exhibited fewer vague category judgments. However, men and women were equally confident in their category judgments, and confidence failed to explain the sex difference in categorization. Men and women appear to categorize the same common objects in systematically different ways.

Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet.

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

Methodological Issues for Psychological Evaluation across the Lifespan of Individuals with a Difference/Disorder of Sex Development.

The aim of the current report is to provide guidance relevant to psychological evaluation for healthcare providers and researchers working in the field of disorders of sexual development (DSD). In doing so, we give careful consideration to methodological issues and limitations that may influence the utility of investigations. For example, rarity and heterogeneity of DSD conditions restrict sample sizes when conducting evaluations aimed at establishing condition-specific psychological outcomes. At the same time, the potential for stigmatization by virtue of conducting psychological evaluations is particularly high given the fundamental contribution of sex and gender to one's sense of self and integrity. This article will provide basic theory for psychological evaluation as well as give a review of specific measures that can be employed for clinical purposes depending on a variety of parameters, including life stage of the patient and goal(s) of the evaluation. Care providers and service users may benefit from guidance in coping with the difficulties inherent in having and/or treating DSD. The potential for identification with the patient with DSD is higher than in other domains of medicine because sexual and gender identities are fundamental to all humans and are continually evolving from a sociological perspective.

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.

Caring for individuals with a difference of sex development (DSD): a Consensus Statement.

The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.

Reduced short term memory in congenital adrenal hyperplasia (CAH) and its relationship to spatial and quantitative performance.

Girls and women with classical congenital adrenal hyperplasia (CAH) experience elevated androgens prenatally and show increased male-typical development for certain behaviors. Further, individuals with CAH receive glucocorticoid (GC) treatment postnatally, and this GC treatment could have negative cognitive consequences. We investigated two alternative hypotheses, that: (a) early androgen exposure in females with CAH masculinizes (improves) spatial perception and quantitative abilities at which males typically outperform females, or (b) CAH is associated with performance decrements in these domains, perhaps due to reduced short-term-memory (STM). Adolescent and adult individuals with CAH (40 female and 29 male) were compared with relative controls (29 female and 30 male) on spatial perception and quantitative abilities as well as on Digit Span (DS) to assess STM and on Vocabulary to assess general intelligence. Females with CAH did not perform better (more male-typical) on spatial perception or quantitative abilities than control females, failing to support the hypothesis of cognitive masculinization. Rather, in the sample as a whole individuals with CAH scored lower on spatial perception (p ≤ .009), a quantitative composite (p ≤ .036), and DS (p ≤ .001), despite no differences in general intelligence. Separate analyses of adolescent and adult participants suggested the spatial and quantitative effects might be present only in adult patients with CAH; however, reduced DS performance was found in patients with CAH regardless of age group. Separate regression analyses showed that DS predicted both spatial perception and quantitative performance (both p ≤ .001), when age, sex, and diagnosis status were controlled. Thus, reduced STM in CAH patients versus controls may have more general cognitive consequences, potentially reducing spatial perception and quantitative skills. Although hyponatremia or other aspects of salt-wasting crises or additional hormone abnormalities cannot be ruled out as potential contributors, elevated GCs appear to be the most likely contributor to reductions in STM. Additional efforts to monitor GC administration protocols may help achieve optimal cognitive outcomes. Educational intervention for individuals with CAH might also be useful.