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.

Personality and congenital adrenal hyperplasia: possible effects of prenatal androgen exposure.

Influences of early androgen exposure on personality were investigated. Participants were either exposed to abnormal levels of androgens prenatally due to congenital adrenal hyperplasia (CAH, 40 females, 29 males), or were unaffected relative controls (29 females, 30 males). Compared to female controls, females with CAH were less tender-minded (p<.001; 16 Personality Factor Inventory (16PF)), and reported greater physical aggression (p=.03; Reinisch Aggression Inventory) and less interest in infants (p<.001; Melson's Questionnaire), but did not differ in dominance (16PF). Males with CAH did not differ from male controls in interest in infants but were less dominant (p=.008), and more tender-minded (p=.033) and reported reduced physical aggression (p=.025). Thus, both males and females with CAH showed alteration in three of the four constructs assessed. Prenatal androgen exposure may shift some, but not all, personality characteristics in the male-typical direction in females. It may also be associated with a decrease in some aspects of male-typical personality development in males, although personality differences in males with CAH could relate to illness.

Motor development in individuals with congenital adrenal hyperplasia: strength, targeting, and fine motor skill.

This study investigated early androgen influence on the development of human motor and visuomotor characteristics. Participants, ages 12-45 years, were individuals with congenital adrenal hyperplasia (CAH), a disorder causing increased adrenal androgen production before birth (40 females, 29 males) and their unaffected relatives (29 females, 30 males). We investigated grip strength and visuomotor targeting tasks on which males generally outperform females, and fine motor pegboard tasks on which females generally outperform males. Physical characteristics (height and weight) were measured to explore whether body parameters could explain differences in motor skills. Females with CAH were stronger and showed better targeting than unaffected females and showed reduced fine visuomotor skill on one pegboard measure, with no difference on the other. Males with CAH were weaker than unaffected males in grip strength but did not differ on the targeting or pegboard measures. Correction for body size could not explain the findings for females, but suggests that the reduced strength of males with CAH may relate to their smaller stature. Further, the targeting advantage in females with CAH persisted following adjustment for their greater strength. Results in females support the hypothesis that androgen may masculinize, or promote, certain motor characteristics at which males excel, and contribute to defeminization of certain fine motor characteristics at which females excel. Thus, these data suggest that organizational effects of androgens on behavior during prenatal life may extend to motor characteristics and may contribute to general sex differences in motor-related behaviors; however, alternative explanations based on activational influences of androgen or altered experiential factors cannot be excluded without further study.

Increased aggression and activity level in 3- to 11-year-old girls with congenital adrenal hyperplasia (CAH).

Experimental research in a wide range of mammals has documented powerful influences of androgen during early development on brain systems and behaviors that show sex differences. Clinical research in humans suggests similar influences of early androgen concentrations on some behaviors, including childhood play behavior and adult sexual orientation. However, findings have been inconsistent for some other behaviors that show sex differences, including aggression and activity level in children. This inconsistency may reflect small sample sizes and assessment limitations. In the present study, we assessed aggression and activity level in 3- to 11-year-old children with CAH (38 girls, 29 boys) and in their unaffected siblings (25 girls, 21 boys) using a questionnaire that mothers completed to indicate current aggressive behavior and activity level in their children. Data supported the hypotheses that: (1) unaffected boys are more aggressive and active than unaffected girls; (2) girls with CAH are more aggressive and active than their unaffected sisters; and (3) boys with and without CAH are similar to one another in aggression and activity level. These data suggest that early androgens have a masculinizing effect on both aggressive behavior and activity level in girls.

Androgens and autistic traits: A study of individuals with congenital adrenal hyperplasia.

Testosterone promotes male-typical neural and behavioral development in non-human mammals. There is growing evidence that testosterone exerts similar influences on human development, although the range of behaviors affected is not completely known. This study examined the hypothesis that autistic traits are increased following prenatal exposure to abnormally high levels of testosterone caused by congenital adrenal hyperplasia (CAH). Sixty individuals with CAH (34 female, 26 male) and 49 unaffected relatives (24 female, 25 male) completed the Autism Spectrum Quotient (AQ). Females with CAH scored significantly higher than unaffected females on total AQ score, largely due to enhanced scores on subscales measuring social skills and imagination. These results suggest that prenatal exposure to high levels of testosterone influences some autistic traits and that hormonal factors may be involved in vulnerability to autism.

Prenatal hormones and postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia.

Toy choices of 3- to 10-year-old children with congenital adrenal hyperplasia (CAH) and of their unaffected siblings were assessed. Also assessed was parental encouragement of sex-typed toy play. Girls with CAH displayed more male-typical toy choices than did their unaffected sisters, whereas boys with and without CAH did not differ. Mothers and fathers encouraged sex-typical toy play in children with and without CAH. However, girls with CAH received more positive feedback for play with girls' toys than did unaffected girls. Data show that increased male-typical toy play by girls with CAH cannot be explained by parental encouragement of male-typical toy play. Although parents encourage sex-appropriate behavior, their encouragement appears to be insufficient to override the interest of girls with CAH in cross-sexed toys.

Classic congenital adrenal hyperplasia and puberty.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications.

Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH).

We assessed core gender identity, sexual orientation, and recalled childhood gender role behavior in 16 women and 9 men with CAH and in 15 unaffected female and 10 unaffected male relatives, all between the ages of 18 and 44 years. Women with congenital adrenal hyperplasia (CAH) recalled significantly more male-typical play behavior as children than did unaffected women, whereas men with and without CAH did not differ. Women with CAH also reported significantly less satisfaction with the female sex of assignment and less heterosexual interest than did unaffected women. Again, men with CAH did not differ significantly from unaffected men in these respects. Our results for women with CAH are consistent with numerous prior reports indicating that girls with CAH show increased male-typical play behavior. They also support the hypotheses that these women show reduced heterosexual interest and reduced satisfaction with the female sex of assignment. Our results for males are consistent with most prior reports that boys with CAH do not show a general alteration in childhood play behavior. In addition, they provide initial evidence that core gender identity and sexual orientation are unaffected in men with CAH. Finally, among women with CAH, we found that recalled male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood. Although prospective studies are needed, these results suggest that those girls with CAH who show the greatest alterations in childhood play behavior may be the most likely to develop a bisexual or homosexual orientation as adults and to be dissatisfied with the female sex of assignment.

Androgenic influences on neural asymmetry: Handedness and language lateralization in individuals with congenital adrenal hyperplasia.

This study tested the hypothesis that prenatal androgen levels influence hand preferences and language lateralization, two manifestations of neural asymmetry. Participants were individuals with congenital adrenal hyperplasia (CAH, a genetic disorder that results in excess adrenal androgen production beginning prenatally) (40 females; 29 males) and their unaffected relatives (29 females; 30 males) who ranged in age from 12-45 years. The Edinburgh-Crovitz Inventory and the performance of five simple tasks (the Handedness Activities Test) were the measures of hand preferences, and a dichotic listening task composed of consonant-vowel nonsense syllables was the measure of language lateralization. No sex differences were observed among relative controls in hand preferences or language lateralization. Male participants with CAH were less consistently right-handed for writing than unaffected male relatives, when those who had been forced to switch writing hands from left to right were considered with left-handers as being not consistently right-handed. There were no other significant differences between individuals with CAH and unaffected relatives. These results do not support the hypothesis that prenatal androgens influence language lateralization, nor do they support the Geschwind-Behan-Galaburda model that posits a key role for testosterone in the development of cognitive problems in males, secondary to changes in hemispheric development and cognitive lateralization. Hormonal influences on handedness, although not always consistent, may be more likely. However, given that sex differences in both language lateralization and handedness are small, it is possible that limited sample size precludes the detection of consistent group differences.

Starting dose of levothyroxine for the treatment of congenital hypothyroidism: a systematic review.

OBJECTIVE: To determine the effect of levothyroxine sodium starting dose on cognitive development, growth, or behavior in children with congenital hypothyroidism identified by neonatal screening. DESIGN: Systematic review of cohort studies. Two analyses were performed: a between-study comparison of mean starting dose with mean developmental score and an analysis of the within-study effects of starting dose on cognitive development, growth, or behavior. RESULTS: The between-study comparison (14 cohort studies based on 1321 patients) found that the standardized mean IQ or developmental quotient scores ranged from 90 to 115 but were not associated with the mean starting dose of levothyroxine (P =.48). The within-study comparison of 4 cohort studies (based on 558 patients) that reported the effect of the starting dose of levothyroxine on cognitive development found no consistent effects. There was weak evidence for an effect of starting dose on growth (1 study) and on behavior problems (1 study). CONCLUSIONS: The evidence for an effect of starting dose of levothyroxine on cognitive development, growth, or behavior is too weak to justify recommendations in favor of high- or standard-dose regimens. More reliable information, based on a randomized controlled trial of starting dose or a meta-analysis of the individual patient data currently available, is required to inform treatment policies.

Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretion.

In humans, GH and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. Substitution therapy is given to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex. However, treatment with twice or three times daily oral hydrocortisone does not mimic physiological adrenal rhythms and may influence the activity of the GH/IGF-I axis. We investigated the pattern of GH and cortisol secretion and the synchrony of joint GH-cortisol secretory dynamics in 15 children with classic 21-hydroxylase deficiency (5 males and 10 females; median age 9.5 yr, range 6.1-11.0 yr) and 28 short normal children (23 males and 5 females; median age 7.7 yr, range 4.9-9.3 yr). All subjects were prepubertal. Serum GH and cortisol concentrations were determined at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol secretory patterns was computed at various time lags covering the 24-h period. Children with CAH had significantly lower mean 24-h serum cortisol concentrations (6.4 +/- 2.2 vs. 10.4 +/- 2.6 microg/dl, P < 0.001), ApEn (GH) (0.64 +/- 0.13 vs. 0.74 +/- 0.17, P = 0.04), ApEn (cortisol) (0.54 +/- 0.13 vs. 1.08 +/- 0.18, P < 0.001) and cross-ApEn values of paired GH-cortisol secretion (0.78 +/- 0.19 vs. 1.05 +/- 0.12, P < 0.001) than normal children. There was no difference in mean 24-h GH concentrations between the two groups (4.5 +/- 2.9 vs. 4.5 +/- 1.9 mU/liter). In children with CAH, a significant positive correlation between GH and cortisol was noted at lag time 0 min (r = 0.299, P < 0.01), peaking at 20 min (r = 0.406, P < 0.0001), whereas in normal children, a significant negative correlation between the two hormones was noted at lag time 0 min (r = -0.312, P < 0.01). The above findings suggest that children with classic CAH have a more regular pattern of GH secretion and a more synchronous joint GH-cortisol secretory dynamics than their normal counterparts. These differences reflect bidirectional interactions between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis in humans, and are likely to evolve as a result of the exogenous administration of hydrocortisone at fixed doses and at specific time intervals, which leads to a more regular pattern in circulating cortisol concentrations, independent of variations in CRH and ACTH concentrations.