Traits of ADHD and autism in girls with a twin brother: a Mendelian randomization study

It has been hypothesized that prenatal exposure to testosterone may be associated with traits of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). We conducted a population-based study of dizygotic female twins to elucidate this hypothesis, assuming that the sex of the co-twin influences the level of prenatal exposure to testosterone. We invited parents of 24,552 3- to 15-year-old twins to answer questionnaires on traits of ADHD and ASD. We analysed the data using a proportional odds model with sex of the co-twin as an instrumental variable for prenatal exposure to testosterone of female twins. We received responses for 6,339 girls from dizygotic twin pairs. Odds ratios for male versus female co-twin were 0.71 (95?% confidence interval 0.61-0.81) for ADHD traits and 0.74 (0.66-0.83) for ASD traits, indicating that a twin brother reduces traits of ADHD and ASD in females. In conclusion, we found that female twins with a twin brother scored significantly lower in parent-reported traits of ADHD and ASD than those with a twin sister. The reason for this may be parental reporting bias, or confounding by unmeasured variables, or a causal effect of an intrauterine environment modified by the sex of the co-twin in the opposite direction of what we expected.     

Sex differences in amphetamine-elicited rotational behavior and the lateralization of striatal dopamine in rats

Sex differences are described in both a lateralized behavior (amphetamine-elicited rotation) and in the lateralization of striatal dopamine (DA) content. Amphetamine (AMPH) elicited significantly more partial turns, total rotations and lateralized (net) rotations in female, than in male rats. The two sexes also differed in their pattern of net rotations over time. In females, but not males, the striatum containing higher DA levels after amphetamine was consistently found to be contralateral to the dominant direction of rotation observed in the first 5 min interval after AMPH. No relationship was found between rotational behavior and medial frontal cortex DA or norepinephrine. The results are discussed in reference to cerebral lateralization in humans, and to possible sex differences in the modulatory effects of gonadal steroid hormones on striatal function.     

Salivary testosterone is related to both handedness and degree of linguistic lateralization in normal women

The aim of this study was to test the hypothesis that individual differences in testosterone (T) are associated with different patterns of linguistic lateralization and hand preference. Twenty left-handed (LH) and 19 right-handed (RH) women filled in a handedness questionnaire and performed a consonant-vowel dichotic listening test (DL-CV). Salivary T was measured by radioimmunoassay (RIA). LH women showed significantly lower mean salivary T than RH women. T levels were negatively correlated with the absolute value of the DL laterality index. Subjects with right ear advantage (REA) were classified into strongly and weakly lateralized following Wexler et al. method (Brain Lang. 13 (1981) 13). When taking into account hand preference, a pattern emerged in that RH-strongly lateralized and LH-weakly lateralized women showed similar T levels. The lowest level appeared for LH-strongly lateralized women and the highest for RH-weakly lateralized women, being significantly different from each other. The results are discussed in terms of several theories that have proposed a link between testosterone and cerebral lateralization.     

Salivary testosterone levels are unrelated to handedness or cerebral lateralization for language

Behavioural and cerebral lateralization are thought to be controlled, at least in part, by prenatal testosterone (T) levels, explaining why sex differences are found in both laterality traits. The present study investigated hormonal effects on laterality using adult salivary T levels, to explore the adequacy of competing theories: the Geschwind, Behan and Galaburda, the callosal, and the sexual differentiation hypotheses. Sixty participants (15 right-handers and 15 left-handers of each sex) participated. Behavioural lateralization was studied by means of hand preference tests (i.e., the Edinburgh Handedness Inventory and the Quantification of Hand Preference test) and a hand skill test (i.e., the Peg-Moving test) whereas cerebral lateralization for language was studied using the Consonant-Vowel Dichotic Listening test and the Visual Half-Field Lexical Decision test. Salivary T and cortisol (C) concentrations were measured by luminescence immunoassay. Canonical correlations did not reveal significant relationships between T levels and measures of hand preference, hand skill, or language laterality. Thus, our findings add to the growing literature showing no relationship between T concentrations with behavioural or cerebral lateralization. It is claimed that prenatal T is not a major determinant of individual variability in either behavioural or cerebral lateralization.     

Sex specific effect of prenatal testosterone on language lateralization in children

Brain lateralization refers to the division of labour between the two hemispheres in controlling a wide array of functions and is remarkably well developed in humans. Based on sex differences in lateralization of handedness and language, several hypotheses have postulated an effect of prenatal exposure to testosterone on human lateralization development, the topic of a long-standing and unresolved debate. Here we demonstrate a clear relationship between prenatal levels of testosterone as assessed from amniotic fluid of healthy pregnant mothers and language lateralization of their offspring at the age of 6 years. Using focused attention conditions in the dichotic listening task, in which the child is instructed to report information from the left ear or the right ear, we were able to differentiate between potential effects of early testosterone on the left hemisphere and effects on inter-hemispheric connectivity. This provides a new method to distinguish between the claims of the different hypotheses. The results suggest that in girls higher prenatal testosterone exposure facilitates left hemisphere language processing, whereas in boys it reduces the information transfer via the corpus callosum.     

Relation of testosterone and hand preference in right-handed young adults to sex and familial sinistrality

The relationship between serum testosterone level and the degree of hand preference was studied in right-handed young adults. Hand preference was assessed by the Edinburgh Handedness Inventory. Serum testosterone level was determined using tritium-marked-radioimmunoassay. There was no significant correlation between these variables in males without FS. In males with FS and in females with and without FS, the serum testosterone levels were found to be negatively linearly correlated with the degree of the right-hand preference. Similar results were obtained with respect to foot and eye preferences. It was concluded that not only prenatal testosterone but adult testosterone also may exert a life long influence on cerebral lateralization; this effect seems to be much more pronounced in the female than male brain, which may exert a female-like pattern under genetic control.     

Fetal testosterone and sex differences in typical social development and in autism

Experiments in animals leave no doubt that androgens, including testosterone, produced by the testes in fetal and/or neonatal life act on the brain to induce sex differences in neural structure and function. In human beings, there is evidence supporting a female superiority in the ability to read nonverbal signals, specific language-related skills, and theory of mind. Even more striking than the sex differences seen in the typical population is the elevated occurrence of social and communicative difficulties in human males. One such condition, autism, occurs four times more frequently in boys than in girls. Recently, a novel theory known as the "extreme male brain" has been proposed. It suggests that the behaviors seen in autism are an exaggeration of typical sex differences and that exposure to high levels of prenatal testosterone might be a risk factor. In this article, we argue that prenatal and neonatal testosterone exposures are strong candidates for having a causal role in sexual dimorphism in human behavior, including social development, and as risk factors for conditions characterized by social impairments, particularly autism spectrum conditions.     

Sex differences in cerebral lateralization in 3- and 4-year old children

Following a procedure described by Jones [12,13] boys and girls, 3 and 4 yr of age, were required to identify the sex of male and female faces tachistoscopically presented to the right and left visual fields. The results were in close conformity to those obtained with adults [12,13]. Boys showed a strong and consistent right visual field advantage in accuracy. Girls showed no strong field advantage. It is argued that cerebral lateralization remains constant across development. Theoretical issues relating to sex differences in cerebral lateralization are discussed.     

Handedness in opposite and same-sex dizygotic twins: testing the testosterone hypothesis

Prenatal exposure to testosterone is proposed to promote development of the right hemisphere and increase the incidence of sinistrality. This proposition was tested by comparing the hand preference of 59 opposite-sex and 61 same-sex dizygotic twins. Because testosterone is thought to pass between twins in utero, it was predicted that females with a male twin would show a high incidence of sinistrality compared to females with a female twin. Similarly, it was predicted that males with a male twin would be more likely to be sinistral than males with a female twin. Measures of the strength of hand preference and the incidence of sinistrality revealed no difference between the opposite and same-sex twins for either sex. The data also failed to confirm reports that first-born twins are more likely to be sinistral than second-born twins. These data add to a growing body of research which is critical of the testosterone hypothesis.     

Sexually dimorphic behavioral and brain asymmetries in neonatal rats: effects of prenatal alcohol exposure

Behavioral and neuroanatomical asymmetries were assessed in 3-day-old male and female rat pups chosen from litters whose dams had received one of 3 prenatal treatments: 35% ethanol-derived calories, pair-fed control, or lab chow control. Behavioral laterality was assessed by observing the preferred tail bias on postnatal (PN) day 1. On PN day 3, brains were sectioned and morphometric analyses conducted for total brain volume, left and right neocortical volumes, and left and right hippocampal volumes. Prenatal alcohol exposure altered the population proportions of left, right and neutral tail biases in male pups on PN day 1. Female pups were affected by both prenatal alcohol exposure and maternal undernutrition/stress of pair-feeding. Prenatal alcohol exposure decreased body weight and total brain volume, but increased the brain volume/body weight ratio compared to both control groups. Prenatal alcohol exposure also reduced the volumes of the hippocampus and neocortex, with the greatest proportional reduction found in the volume of the anterior neocortex. A left-right anterior neocortical asymmetry was observed, with tail bias, prenatal treatment and sex all significant factors. Alcohol-exposed males showed a 'feminized' asymmetry. These results demonstrate that a sexually dimorphic cerebral asymmetry can be detected at birth in rats; this asymmetry appears to be related to a postural position bias. The reversal of normal interhemispheric relations by prenatal alcohol exposure in male offspring suggested that the in utero hormonal milieu modulates the development of cerebral lateralization.     

Alcohol dependence in same-sex and opposite-sex twins

Males with a female co-twin are more likely to become alcohol-dependent than males with a male co-twin. According to the twin testosterone transfer model, this finding can be interpreted as indirect evidence for a role of prenatal testosterone in alcohol dependence.     

Pubertal testosterone predicts mental rotation performance of young adult males

Robust sex differences in some spatial abilities that favor males have raised the question of whether testosterone contributes to those differences. There is some evidence for prenatal organizational effects of testosterone on male-favoring spatial abilities, but not much is known about the role of pubertal testosterone levels on adult cognitive abilities. We studied the association between pubertal testosterone (at age 14) and cognitive performance in young adulthood (at age 21-23), assessing male-favoring, female-favoring, and sex-neutral cognitive domains in a population-based sample of 130 male and 178 female twins. Pubertal testosterone was negatively associated with performance in the Mental Rotation Test in young adult men (r=-.27), while among women no significant associations between testosterone and cognitive measures were detected. The significant association among men remained after controlling for pubertal development. Confirmatory within-family comparisons with one-sided significance testing yielded a negative correlation between twin pair differences in testosterone levels and Mental Rotation Test performances in 35 male twin pairs (r=-.32): the twin brother with higher testosterone performed less well on the Mental Rotation Test. That association was evident in 18 pairs of dizygotic male twin pairs (r=-.42; analysis controlling for shared environmental effects). In contrast, the association of differences was not evident among 17 monozygotic male twin pairs (r=-.07; analysis controlling for shared genetic influences). Results suggest that pubertal testosterone levels are related specifically to male-favoring spatial ability and only among men. Within-family analyses implicated possible shared genetic effects between pubertal testosterone and mental rotation ability.     

Development of lateralized behaviour in the human fetus from 12 to 27 weeks' gestation

Handedness is the most prominent manifestation of behavioural lateralization in the human population. However, little is known about its ontogeny. This study examined the prenatal development of behavioural lateralization by observing, longitudinally, the occurrence of left- and right-arm movements in 17 human fetuses at 3-week intervals from 12 to 27 weeks gestational age. Fetuses exhibited significantly more right-arm movements than left-arm movements at every gestational age. Throughout all periods of observation, 83.3% of fetuses showed more right-arm than left-arm movements. The number of arm movements observed peaked at 15 to 18 weeks' gestation and declined rapidly in mid-gestation. The occurrence of laterality in early gestation indicates that asymmetric behaviour is probably under muscular or spinal, rather than cortical, control and points to a 'genetic' origin for such behaviour. The presence of lateralized motor behaviour in early gestation suggests it may have a potential causative role for subsequent lateralized behaviour and asymmetric brain development.     

Association between co-twin sex and eating disorders in opposite sex twin pairs: evaluations in North American, Norwegian, and Swedish samples

ObjectiveThese three studies examined the hypothesis that prenatal exposure to sex hormones influences twins' risk for eating disorders based on co-twin sex, such that individuals with a female co-twin would be more likely than individuals with a male co-twin to meet diagnostic criteria for an eating disorder.MethodsMale and female twins from the United States (N=2607), Norway (N=2796) and Sweden (N=16,458) with known co-twin sex and zygosity were assessed for eating disorders.ResultsIn the U.S. and Swedish samples, sex was significantly associated with eating disorder diagnoses, and although co-twin sex was not associated with eating disorders overall, it was associated with broadly defined bulimia nervosa in the Swedish sample. The effects for bulimia were not sustained when monozygotic twins were excluded, suggesting that the effects of prenatal sex hormones play a minor role in influencing eating disorders. Sex and co-twin sex were not associated with eating disorders in the Norwegian sample.ConclusionThe prenatal sex hormone hypothesis, which proposes that prenatal hormone exposure is associated with later eating disorder symptomatology, was not supported in these three population-based twin samples.     

Laterality associated with sexual dimorphism in the volume of the mouse hypogastric ganglion

The volume of the hypogastric ganglion was investigated in male, female, and prenatally androgen-exposed female newborn mice. Two milligram testosterone propionate was injected into pregnant ICR mice from days 14 to 16 of gestation. The volume of the ganglia on both sides in intact male neonates was significantly larger than that in female neonates. The volume of ganglia in testosterone-exposed females was significantly larger than those in intact females, but did not attain the male volume. In intact males, the ganglion on the left side was significantly larger than on the right. This left-right difference in the volume of the ganglia was not recognized in the intact or TP-exposed females. These results suggest that sex difference and lateralization of the volume of the hypogastric ganglion were highly dependent on the prenatal sex hormone environment.     

Intrauterine position effects

A review of the literature suggests that individual variability in sex-related traits may be influenced by variations in hormonal exposure during fetal development. In litter-bearing mammals, fetuses develop in utero and may be subjected to differing hormonal environments based upon the sex of neighboring fetuses. Female fetuses developing between two males tend to show masculinized anatomical, physiological and behavioral traits as adults. Female fetuses developing without adjacent males, on the other hand, tend to show more feminized traits as adults. These traits include permanently altered hormone levels, reproductive organs, aggressive behaviors, secondary sex ratios and susceptibility to endocrine disruption. This intrauterine effect is due to the transfer of testosterone from male fetuses to adjacent fetuses. While these effects have been most clearly demonstrated in mice, other rodents and swine also show intrauterine position (IUP) effects. Some of these effects are similar to the influence of prenatal stress on adult phenotypes. A few reports on human twins suggest that variability in some masculine and feminine traits may be due to intrauterine hormonal signals. IUP effects may impact a number of scientific fields of research such as endocrine disruption, toxicology, population biology, animal production and health.     

Manual proficiency in Cattle's Intelligence Test in left-handed male and female subjects

The relationship between nonverbal intelligence (spatial reasoning) and manual proficiency was studied in male and female left-handers. Manual proficiency was assessed by measuring the speed and accuracy in performing the dot-filling test. Nonverbal intelligence was assessed by Cattle's Culture Fair Intelligence Test. Females were found to be better than males in left-hand performance, and were more lateralized than males in manual proficiency. No significant sex difference could be established in right-hand performance. The right-hand skill was positively correlated to test intelligence (p less than 0.001). There was a negative correlation between the left- minus right-hand skill difference and the scores for nonverbal intelligence (p less than 0.001). The left-hand skill did not show any correlation with nonverbal IQ. It was concluded that the left-hemisphere is of utmost importance even for nonverbal intelligence; strong cerebral lateralization is disadvantageous for spatial reasoning.     

Cortical and striatal mu-opioid receptors are altered by gonadal hormone treatment but not by prenatal morphine exposure in adult male and female rats

The cerebral cortex (CX), cingulate CX (cgCX), and striatum (STR) play an important role in locomotion, cognition, emotion, and reward-motivated behaviors, and are altered by prenatal morphine exposure. We have demonstrated that delta-opioid receptors in the CX and STR of adult male and female rats are altered by prenatal morphine exposure and gonadal hormonal treatment. Because morphine binds with greater affinity to mu- than delta-opioid receptors, the present study examined the effect of prenatal morphine exposure on mu-opioid receptor density in the CX, cgCX, and STR of adult male and female rats using receptor autoradiography. In Experiment 1, three groups of adult male rats were analyzed: intact, gonadally intact; GNX, gonadectomized; and TP, GNX and testosterone propionate (TP)-treated. In Experiment 2, four groups of adult females were analyzed: OVX, ovariectomized; EB, OVX and estradiol benzoate (EB)-treated; P, OVX and progesterone (P)-treated; and EB+P, OVX and EB- and P-treated. In male rats, GNX and TP males had lower mu-opioid receptor densities in all three brain regions than gonadally intact males regardless of prenatal drug exposure. In female rats, OVX, EB+P-treated females had lower mu-opioid receptor density in the STR than OVX only females regardless of prenatal drug exposure. There were no drug or gonadal hormone effects in the CX or in the cgCX of female rats. Thus, the present study demonstrates that gonadal hormones, and not prenatal morphine exposure, alter the density of mu-opioid receptors in the CX, cgCX, and STR of adult male and female rats.     

Serum testosterone levels in male and female subjects with standard and anomalous dominance.

Serum testosterone levels were determined in female and male subjects. Hand preference was assessed by the Edinburgh Handedness Inventory. Subjects with anomalous dominance (left-handers, mixed-handers, and right-handers with familial sinistrality) were compared to subjects with standard dominance (right-handers without familial sinistrality). The mean serum testosterone levels were found to be significantly higher in subjects with anomalous dominance than those with standard dominance. It was concluded that the results are in accord with the testosterone hypothesis of cerebral lateralization.     

Gender-related differences in lateralization of hippocampal activation and cognitive strategy

Gender-related differences in brain activation patterns and their lateralization associated with cognitive functions have been reported in the field of language, emotion, and working memory. Differences have been hypothesized to be due to different cognitive strategies. The aim of the present study was to test whether lateralization of brain activation in the hippocampi during memory processing differs between the sexes. We acquired functional magnetic resonance imaging data from healthy female and male study participants performing a spatial memory task and quantitatively assessed the lateralization of hippocampal activation in each participant. Hippocampal activation was significantly more left lateralized in women, and more right lateralized in men. Correspondingly, women rated their strategy as being more verbal than men did.