Since the ratio of the second-to-fourth finger length was first proposed as a marker for prenatal androgen action in 1998, over 100 studies have been published that have either further tested the association between the digit ratio and prenatal androgens, or employed digit ratios as a marker to investigate the association between prenatal androgens and a variety of outcomes, including behavior, fertility, and disease risks. Despite the clear demand for an adult marker of prenatal androgen action and increased use of digit ratios as such a marker, its validity remains controversial. This review (1) evaluates current evidence for the relationship between digit ratios and prenatal androgens (using experimentation with animal models, amniotic testosterone, and congenital adrenal hyperplasia case-control studies), (2) describes opportunities for future validation tests, and (3) compares the potential advantages and disadvantages of digit ratio measures with more established methods for studying the effects of prenatal androgens.
Polycystic ovary syndrome (PCOS) is heterogeneous in its clinical presentation and four major phenotypes have been identified. The precise etiology of PCOS is unknown; however, variable exposure to prenatal androgens may be responsible for the spectrum of endocrine and metabolic disturbances characteristic of this syndrome. Since prenatal testosterone exposure is known to decrease the ratio of the second to fourth finger lengths (2D:4D), we characterized the left and right hand 2D:4D in women with clinical variants of PCOS. We hypothesized that if prenatal androgens were involved in the development of the phenotypic spectrum of PCOS, then lower 2D:4D would be differentially expressed among clinical variants of the syndrome.
Digit ratios were determined in 98 women diagnosed with PCOS by the 2003 international consensus guidelines and in 51 women with regular menstrual cycles, no clinical or biochemical signs of hyperandrogenism and normal ovarian morphology. Women with PCOS were categorized into four clinical phenotypes (i.e. Frank, Non-PCO, Ovulatory and Mild) and 2D:4D among groups were compared by Tukey–Kramer multiple comparisons tests.
Left (P = 0.77) and right (P = 0.68) hand 2D:4D were similar among the four clinical phenotypes and no phenotype of PCOS demonstrated a 2D:4D that differed from controls (Left Hand, P = 0.44 and Right Hand, P = 0.75).
Women with PCOS do not demonstrate finger length patterns that are consistent with increased prenatal androgen exposure. These findings do not preclude a role for prenatal androgens in the development of PCOS; however, low 2D:4D are not a characteristic of PCOS.
PMID: 19855107 CAMSID: cams561
digit ratios; polycystic ovary syndrome; prenatal androgen exposure
We investigated the relationship between patterns of sex and hand differences in circadian wrist activity and digit ratio, a marker for prenatal androgen exposure. If the contribution of prenatal androgen exposure to sex differences in digit ratio underlies sex differences in circadian wrist activity, we predict that patterns of wrist activity will be correlated with digit ratio.
Bilateral wrist activity of male and female college students was measured for three consecutive days. Digit ratio was obtained from photocopy measurements of the second and fourth fingers of each subject.
Males had lower digit ratios with more pronounced differences on the right hand. Female acrophase occurred earlier than male acrophase. There was more activity in the right hand and right hand activity peaked before the left. Digit ratio was not correlated with any measure of wrist activity. An analysis of activity by age revealed that younger female students exhibited more male-like activity patterns.
Sex and hand differences for digit ratio and acrophase replicated previous findings. The lack of correlation between digit ratio and patterns of wrist activity suggests that sexually dimorphic circadian activity develops independently from the mechanisms of hormone exposure that cause sex differences in digit ratio.
Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population.
Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data.
The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman’s rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have ‘high’ scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females.
These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.
Autism; Testosterone; Prenatal; Perinatal; Autistic-like traits
The second to fourth (2D:4D) digit ratio, a sexually dimorphic, phenotypic characteristic putatively associated with perinatal androgen action, has been used to evaluate the hypothesized relation between prenatal hormonal factors and a variety of sexually dimorphic behaviors, including sex-linked psychopathology. Smaller digit ratios, suggestive of stronger perinatal androgen action, have been associated with male-linked disorders (e.g., autism), and larger digit ratios, suggestive of weaker perinatal androgen action, have been associated with female-linked disorders (e.g., depression and eating disorders). To evaluate the possible relation between digit ratio and another traditionally female-linked disorder, anxiety, 2D:4D ratios were measured in a non-clinical sample (58 men, 52 women). Participants also completed a battery of anxiety and gender role measures and performed two spatial/cognitive tasks typically showing a male advantage (mental rotation and targeting) and two tasks typically showing a female advantage (location memory and spatial working memory). Men with a more feminine pattern of sex-linked traits and behaviors (including digit ratios) reported greater anxiety. In contrast, greater anxiety in women was associated with both female-typical and male-typical traits and behaviors, and no significant association between digit ratio and anxiety was found. This pattern of results suggests that the development of anxiety is multiply determined, with contributing factors varying by sex.
anxiety; sex-linked behavior; 2D:4D ratio; gonadal hormones
Little is known about the female presentation of autism spectrum disorder (ASD) during early childhood. We investigated sex differences in developmental profiles using the Mullen Scales of Early Learning, autistic symptoms on the ADOS-G, and coexisting behavior problems on the CBCL in 157 boys and 42 girls with ASD aged 1.5–3.9 years. Overall, boys and girls evidenced a markedly similar pattern of developmental profiles, autism symptoms, and coexisting behavior problems, although subtle differences exist. Boys and girls evidenced a similar pattern of developmental strengths and weaknesses. Girls with ASD evidenced greater communication deficits than boys and boys evidenced more restricted, repetitive, and stereotyped behavior than girls. Girls exhibited more sleep problems and anxious or depressed affect than boys.
Autism; Sex; Girl; Developmental functioning; Behavior problems
Background: Reported associations between gestational tobacco exposure and autism spectrum disorders (ASDs) have been inconsistent.
Objective: We estimated the association between maternal smoking during pregnancy and ASDs among children 8 years of age.
Methods: This population-based case–cohort study included 633,989 children, identified using publicly available birth certificate data, born in 1992, 1994, 1996, and 1998 from parts of 11 U.S. states subsequently under ASD surveillance. Of these children, 3,315 were identified as having an ASD by the active, records-based surveillance of the Autism and Developmental Disabilities Monitoring Network. We estimated prevalence ratios (PRs) of maternal smoking from birth certificate report and ASDs using logistic regression, adjusting for maternal education, race/ethnicity, marital status, and maternal age; separately examining higher- and lower-functioning case subgroups; and correcting for assumed under-ascertainment of autism by level of maternal education.
Results: About 13% of the source population and 11% of children with an ASD had a report of maternal smoking in pregnancy: adjusted PR (95% confidence interval) of 0.90 (0.80, 1.01). The association for the case subgroup autistic disorder (1,310 cases) was similar: 0.88 (0.72, 1.08), whereas that for ASD not otherwise specified (ASD-NOS) (375 cases) was positive, albeit including the null: 1.26 (0.91, 1.75). Unadjusted associations corrected for assumed under-ascertainment were 1.06 (0.98, 1.14) for all ASDs, 1.12 (0.97, 1.30) for autistic disorder, and 1.63 (1.30, 2.04) for ASD-NOS.
Conclusions: After accounting for the potential of under-ascertainment bias, we found a null association between maternal smoking in pregnancy and ASDs, generally. The possibility of an association with a higher-functioning ASD subgroup was suggested, and warrants further study.
autism; epidemiology; intellectual disability; surveillance; tobacco
Early androgen exposure is known to have long-lasting effects on phenotype, behaviour and even fitness, but difficulties in measuring the exposure hinders the study of its importance in evolutionary context. Digit ratios have been highlighted as a potential easy-to-measure indicator of early steroid exposure, as they have been suggested to reflect steroid, mainly testosterone levels during prenatal development. However, evidence for digit ratios reflecting early steroid levels is weak, as experimental studies, especially in wild populations, are scarce. We studied the association between maternally derived yolk androgens and digit ratios (2D:4D, 2D:3D and 3D:4D) using both correlative data and a rather high level of experimental elevation of yolk androgens in a passerine bird, the pied flycatcher (Ficedula hypoleuca). We also examined whether digit ratios have indicator value in an evolutionary context by studying correlations between digit ratios and reproductive traits, secondary sexual traits and exploratory behaviour. We did not find any association between digit ratios and yolk androgen level either in correlative or experimental data. Digit ratios were neither related to any of the reproductive and secondary sexual traits or exploratory behaviour measured. There was, however, a sex difference in 2D:3D and 3D:4D of adult birds (due to second and fourth digits being shorter in females), which was not apparent in fledglings or captivity-raised juveniles. This suggests that either the sex difference may develop as late as during the sexual maturation for breeding. These results indicate that, in this species, digit ratios are not reliable markers of maternally derived yolk androgen exposure and that they bear little relevance as correlates of the adaptive traits we measured.
2D:4D; Bird; Fitness; Testosterone; Maternal effects; Sexual dimorphism
The second to fourth digit ratio (2D∶4D) is sexually differentiated in a variety of species, including humans, rats, birds, and lizards. In humans, this ratio tends to be lower in males than in females. Lower digit ratios are believed to indicate increased prenatal testosterone exposure, and are associated with more masculinized behavior across a range of traits. The story seems more complicated in laboratory mice. We have previously shown that there is no sex difference in the digit ratios of inbred mice, but found behavioral evidence to suggest that higher 2D∶4D is associated with more masculinized behaviors. Work examining intrauterine position effects show that neighbouring males raise pup digit ratio, suggesting again that higher digit ratios are associated with increased developmental androgens. Other work has suggested that masculinization is associated with lower digit ratios in lab mice. Here, we examine the fore- and hindlimb digit ratios of 20 inbred mouse strains. We find large inter-strain differences, but no sexual dimorphism. Digit ratios also did not correlate with mice behavioral traits. This result calls into question the use of this trait as a broadly applicable indicator for prenatal androgen exposure. We suggest that the inbred mice model presents an opportunity for researchers to investigate the genetic, and gene-environmental influence on the development of digit ratios.
Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.
Repetitive; Primate; Macaque; Macaca mulatta; Activity; Asperger syndrome
Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction.
Prenatal testosterone excess programs an array of adult reproductive disorders including luteinizing hormone excess, functional hyperandrogenism, neuroendocrine defects, polycystic ovarian morphology, and corpus luteum dysfunction, culminating in early reproductive failure. Polycystic ovarian morphology originates from enhanced follicular recruitment and follicular persistence. We tested to determine whether prenatal testosterone treatment, by its androgenic actions, enhances follicular recruitment, causes early depletion of follicular reserve, and disrupts the ovarian architecture. Pregnant sheep were given twice-weekly injections of testosterone or dihydrotestosterone (DHT), a nonaromatizable androgen, from Days 30 to 90 of gestation. Ovaries were obtained from Day-90 and Day-140 fetuses, and from 10-mo-old females during a synchronized follicular phase (n = 5–9 per treatment). Stereological techniques were used to quantify changes in ovarian follicle/germ cell populations. Results revealed no differences in numbers of oocytes and follicles between the three groups on Fetal Day 90. Greater numbers of early growing follicles were found in prenatal testosterone- and DHT-treated fetuses on Day 140. Increased numbers of growing follicles and reduced numbers of primordial follicles were found in 10-mo-old, prenatal testosterone-treated females, but not in those treated with DHT. Antral follicles of prenatal testosterone-treated females, but not those treated with DHT, manifested several abnormalities, which included the appearance of hemorrhagic and luteinized follicles and abnormal early antrum formation. Both treatment groups showed morphological differences in the rete ovarii. These findings suggest that increased follicular recruitment and morphologic changes in the rete ovarii of prenatal testosterone-treated females are facilitated by androgenic programming, but that postpubertal follicular growth, antral follicular disruptions, and follicular depletion largely occur through estrogenic programming.
Prenatal testosterone excess disrupts follicular dynamics with early disruptions programmed by its androgenic actions and subsequent antral follicular disruptions and follicular depletion largely via estrogenic programming.
developmental biology; follicle; follicular development; folliculogenesis; ovary; PCOS; reproductive aging
Exposure to prenatal androgens affects both future behavior and life choices. However, there is still relatively limited evidence on its effects on academic performance. Moreover, the predicted effect of exposure to prenatal testosterone (T)–which is inversely correlated with the relative length of the second to fourth finger lengths (2D:4D)–would seem to have ambiguous effects on academic achievement since traits like aggressiveness or risk-taking are not uniformly positive for success in school. We provide the first evidence of a non-linear, quadratic, relationship between 2D:4D and academic achievement using samples from Moscow and Manila. We also find that there is a gender differentiated link between various measures of academic achievement and measured digit ratios. These effects are different depending on the field of study, choice of achievement measure, and use of the right hand or left digit ratios. The results seem to be asymmetric between Moscow and Manila where the right (left) hand generates inverted-U (U-shaped) curves in Moscow while the pattern for hands reverses in Manila. Drawing from unusually large and detailed samples of university students in two countries not studied in the digit literature, our work is the first to have a large cross country comparison that includes two groups with very different ethnic compositions.
A steady increase in the prevalence of autism spectrum disorders (ASD) has been reported in studies based on different methods, requiring adjustment for participation and missing data. Recent studies with high ASD prevalence rates rarely report on co-occurring medical conditions. The aim of the study was to describe the prevalence of clinically confirmed cases of ASD in Iceland and concomitant medical conditions.
The cohort is based on a nationwide database on ASD among children born during 1994–1998.
A total of 267 children were diagnosed with ASD, 197 boys and 70 girls. Only clinically confirmed cases were included. All received physical and neurological examination, standardised diagnostic workup for ASD, as well as cognitive testing. ASD diagnosis was established by interdisciplinary teams. Information on medical conditions and chromosomal testing was obtained by record linkage with hospital registers.
Two tertiary institutions in Iceland. The population registry recorded 22 229 children in the birth cohort.
Prevalence of all ASD was 120.1/10 000 (95% CI 106.6 to 135.3), for boys 172.4/10 000 (95% CI 150.1 to 198.0) and for girls 64.8/10 000 (95% CI 51.3 to 81.8). Prevalence of all medical conditions was 17.2% (95% CI 13.2 to 22.2), including epilepsy of 7.1% (95% CI 4.6 to 10.8). The proportion of ASD cases with cognitive impairment (intellectual quotient <70) was 45.3%, but only 34.1% were diagnosed with intellectual disability (ID). Children diagnosed earlier or later did not differ on mean total score on a standardised interview for autism.
The number of clinically verified cases is larger than in previous studies, yielding a prevalence of ASD on a similar level as found in recent non-clinical studies. The prevalence of co-occurring medical conditions was high, considering the low proportion of ASD cases that also had ID. Earlier detection is clearly desirable in order to provide counselling and treatment.
Epidemiology; Public health
The ratio of the length of the second digit (index finger) divided by the fourth digit (ring finger) tends to be lower in men than in women. This 2D∶4D digit ratio is often used as a proxy for prenatal androgen exposure in studies of human health and behavior. For example, 2D∶4D ratio is lower (i.e. more “masculinized”) in both men and women of greater physical fitness and/or sporting ability. Lab mice have also shown variation in 2D∶4D as a function of uterine environment, and mouse digit ratios seem also to correlate with behavioral traits, including daily activity levels. Selective breeding for increased rates of voluntary exercise (wheel running) in four lines of mice has caused correlated increases in aerobic exercise capacity, circulating corticosterone level, and predatory aggression. Here, we show that this selection regime has also increased 2D∶4D. This apparent “feminization” in mice is opposite to the relationship seen between 2D∶4D and physical fitness in human beings. The present results are difficult to reconcile with the notion that 2D∶4D is an effective proxy for prenatal androgen exposure; instead, it may more accurately reflect effects of glucocorticoids, or other factors that regulate any of many genes.
Background: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features.
Objectives: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk.
Methods: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism.
Discussion: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition.
Conclusions: In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.
autism spectrum disorders; carbamate; gene–environment interaction; immune; mitochondria; neuroexcitation; organochlorine; organophosphate; oxidative stress; pesticide; pyrethroid
Background and Aim
Exposure to stressful life events during pregnancy has been suggested as a potential risk factor for offspring Autism Spectrum Disorders (ASD), but the literature is limited and inconsistent. We tested the hypothesis that maternal exposure to stressful life events would be associated with increased risks of offspring ASD, and that these risks would be highest for exposures during the prenatal period.
Methods and Results
We used prospectively collected data from two large population based studies in Sweden and England. In the Swedish study of 4429 ASD cases and 43277 controls, our exposure comprised the occurrence of any severe life event before and during pregnancy and the child's early life. In the English study (maximum n = 11554, ASD n = 72), we studied the risk of offspring ASD in relation to a combined maternal exposure to multiple (up to 42) common and rare life events, as well as their perceived impact upon the mother during pregnancy and early life. In crude and adjusted regression analyses in both studies, we found no evidence of an association between prenatal life events, or their number and perceived impact and the risk of offspring ASD. Sub-group analysis of ASD with and without intellectual disability in the Swedish study yielded similar results.
We found no evidence to support the hypotheses that exposure to stressful life events during the prenatal period is associated with an increased risk of offspring ASD.
Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders, including ASDs (autism spectrum disorders). In this study, we examined the combinatorial effect of two factors thought to be involved in autism – reduction in the expression of the extracellular matrix protein reelin and prenatal exposure to an organophosphate pesticide, CPO (chlorpyrifos oxon). Mice with reduced reelin expression or prenatal exposure to CPO exhibited subtle changes in ultrasound vocalization, open field behaviour, social interaction and repetitive behaviour. Paradoxically, mice exposed to both variables often exhibited a mitigation of abnormal behaviours, rather than increased behavioural abnormalities as expected. We identified specific differences in males and females in response to both of these variables. In addition to behavioural abnormalities, we identified anatomical alterations in the olfactory bulb, piriform cortex, hippocampus and cerebellum. As with our behavioural studies, anatomical alterations appeared to be ameliorated in the presence of both variables. While these observations support an interaction between loss of reelin expression and CPO exposure, our results suggest a complexity to this interaction beyond an additive effect of individual phenotypes.
autism; cerebellum; hippocampus; olfactory bulb; reeler; social interaction; ultrasonic communication; ACHE, acetylcholinesterase; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CPO, chlorpyrifos oxon; ECL, enhanced chemiluminescence; WT, wild-type
This study aims to investigate the association between prenatal exposure to terbutaline and other β2 adrenergic receptor (B2AR) agonists and autism spectrum disorders (ASDs). The methodology used is a case–control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 291) were children with an ASD diagnosis; controls (n = 284) were children without ASDs, randomly sampled and frequency-matched to cases on sex, birth year, and delivery hospital. Exposure to B2AR agonists during 30 days prior to conception and each trimester of pregnancy was ascertained from prenatal medical records and health plan databases. The frequency of exposure to any B2AR agonist during pregnancy was similar for mothers of children with ASD and mothers of controls (18.9% vs. 14.8%, P = 0.19). Exposure to B2AR agonists other than terbutaline was not associated with an increased risk for ASDs. However, terbutaline exposure for >2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (ORadj = 4.4; 95% confidence interval, 0.8–24.6). This analysis does not offer evidence linking B2AR exposure in pregnancy with autism risk. However, exposure to terbutaline during the third trimester for >2 days may be associated with an increased risk of autism. Should this result be confirmed in larger samples, it would point to late pregnancy as an etiologic window of interest in autism risk factor research.
Asthma; Beta 2 adrenergic agonist; B2AR agonists; Autistic; Perinatal risk factors; Terbutaline
Only case reports have described the co-occurrence of gender identity disorder (GID) and autism spectrum disorders (ASD). This study examined this co-occurrence using a systematic approach. Children and adolescents (115 boys and 89 girls, mean age 10.8, SD = 3.58) referred to a gender identity clinic received a standardized assessment during which a GID diagnosis was made and ASD suspected cases were identified. The Dutch version of the Diagnostic Interview for Social and Communication Disorders (10th rev., DISCO-10) was administered to ascertain ASD classifications. The incidence of ASD in this sample of children and adolescents was 7.8% (n = 16). Clinicians should be aware of co-occurring ASD and GID and the challenges it generates in clinical management.
Autism spectrum disorder; Gender identity disorder; Co-occurrence; Incidence
Mammals, including humans, show sex differences in juvenile play behavior. In rodents and nonhuman primates, these behavioral sex differences result, in part, from sex differences in androgens during early development. Girls exposed to high levels of androgen prenatally, because of the genetic disorder congenital adrenal hyperplasia, show increased male-typical play, suggesting similar hormonal influences on human development, at least in females. Here, we report that fetal testosterone measured from amniotic fluid relates positively to male-typical scores on a standardized questionnaire measure of sex-typical play in both boys and girls. These results show, for the first time, a link between fetal testosterone and the development of sex-typical play in children from the general population, and are the first data linking high levels of prenatal testosterone to increased male-typical play behavior in boys.
Findings regarding phenotypic differences between boys and girls with ASD are mixed. We compared autism and internalizing symptoms in a sample of 8-18 year-old girls (n = 20) and boys (n = 20) with ASD and typically developing (TYP) girls (n = 19) and boys (n = 17). Girls with ASD were more impaired than TYP girls but did not differ from boys with ASD in autism symptoms. In adolescence, girls with ASD had higher internalizing symptoms than boys with ASD and TYP girls, and higher symptoms of depression than TYP girls. Girls ages 8-18 with ASD resemble boys with ASD and not TYP girls, and appear to be at increased risk for affective symptoms in the teen years.
Sex differences; Autism; Girls; Internalizing psychopathology; Gender paradox
Autism Spectrum Disorder (ASD) is the collective term for neurodevelopmental disorders characterized by qualitative impairments in social interaction, communication, and a restricted range of activities and interests. Many countries, including Australia, have reported a dramatic increase in the number of diagnoses over the past three decades, with current prevalence of ASD at 1 in every 110 individuals (~1%). The potential role for an immune-mediated mechanism in ASD has been implicated by several studies, and some evidence suggests a potential link between prenatal infection-driven inflammation and subsequent development of ASD. Furthermore, a modest number of contemporary studies have reported a markedly increased prevalence of ASD in children born preterm, who are at highest risk of exposure to perinatal inflammation. However, the mechanisms that underpin the susceptibility to infection-driven inflammation during pregnancy and risk of preterm birth, and how these intersect with the subsequent development of ASD in the offspring, is not understood. This review aims to summarize and discuss the potential mechanisms and evidence for the role of prenatal infection on the central nervous system, and how it may increase the susceptibility for ASD pathogenesis in children born preterm.
preterm; autism spectrum disorders; prenatal infection; immunology
Autism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk.
To explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates – a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med.
Using all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country’s circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision.
This ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism.
Paracetamol; Acetaminophen; Autism spectrum disorder; Sulfation; Glucuronidation; Pro-inflammatory cytokines
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes.
We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells.
Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.
Allergy; Autism; Brain; Inflammation; Mast cells; Prematurity; Stress