Is there an association between prenatal testosterone and autistic traits in adolescents?

Prenatal testosterone (pT) is a crucial component in physiological masculinization in humans. In line with the Prenatal Sex Steroid Theory of autism, some studies have found a positive correlation between pT and autistic traits in childhood. However, effects in adolescence have not been explored. Hormonal and environmental changes occurring during puberty may alter the strength or the nature of prenatal effects on autistic traits. The current study examines if pT relates to autistic traits in a non-clinical sample of adolescents and young adults (N = 97, 170 observations; age 13-21 years old). It also explores pT interactions with pubertal stage and timing. PT concentrations were measured from amniotic fluid extracted in the 2nd trimester of gestation via amniocentesis conducted for clinical purposes. Autistic traits were measured by self- and parent-reports on the Autism Spectrum Quotient (AQ) which provides a total score and 5 sub-scores (social skills, communication, imagination, attention switching and attention to detail). Self-reported pubertal stage was regressed on age to provide a measure of relative timing. We found no statistical evidence for a direct association between pT and autistic traits in this adolescent sample (males, females or full sample). Exploratory analyses suggested that pT correlated positively with autistic traits in adolescents with earlier puberty-onset, but statistical robustness of this finding was limited. Further exploratory post-hoc tests suggested the pT-by-pubertal timing interaction was stronger in males relative to females, in self-reported compared to parent-reported AQ and specifically for social traits. These findings require replication in larger samples. Findings have implications for understanding the effects of pT on human behavior, specifically existence of effects in adolescence

Is the association between mothers’ autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

Background: Previous studies showed that there is a positive association between mothers’ and children’s autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). Method: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). Result: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; βadjusted = 0.20, p &lt; 0.01), in early childhood (Generation R; βadjusted = 0.19, p &lt; 0.01), and in early adolescence (Generation R; βadjusted = 0.16, p &lt; 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (βadjusted = 0.03, p &lt; 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. Conclusion: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.</p

Is the association between mothers’ autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

Background: Previous studies showed that there is a positive association between mothers’ and children’s autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). Method: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). Result: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; βadjusted = 0.20, p &lt; 0.01), in early childhood (Generation R; βadjusted = 0.19, p &lt; 0.01), and in early adolescence (Generation R; βadjusted = 0.16, p &lt; 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (βadjusted = 0.03, p &lt; 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. Conclusion: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.</p

Foetal oestrogens and autism

Funder: Autism Research Trust (ART), RG72423Funder: Peterhouse Research Studentship, Reference: PS2017-8 / at768Funder: University of Cambridge | Trinity College, University of Cambridge; doi: https://doi.org/10.13039/501100000727Abstract: Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n = 98 cases, n = 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function

Medical symptoms and conditions in autistic women.

Funder: National Institute for Psychobiology in Israel, Hebrew University of Jerusalem; FundRef: https://doi.org/10.13039/501100001739Funder: Templeton World Charitable FoundationFunder: NIHR Biomedical Research Centre in CambridgeFunder: Autism Research TrustSex-steroids, such as testosterone, are thought to be one of the biological factors implicated in autism. This relies on the sex bias in the diagnosis of autism (boys are approximately four times more likely to be diagnosed than girls) and findings of associations with fetal testosterone levels in traits and abilities related to autism. The current study aimed to examine the association between medical conditions and physical symptoms, which tend to manifest in adulthood, and autism in females. Moreover, we examined their association with autistic traits throughout the spectrum. We focused on autistic women because there is little research focusing on the healthcare needs of autistic women, but those that exist suggest heightened vulnerability, and lower access to medical care. We find that conditions related to steroid hormones function are more frequent in autistic women and that they correlate with autistic traits. Specifically, we found that body mass index, reproductive system diagnoses, prediabetes symptoms, irregular puberty onset, and menstrual irregularities were significantly more frequent in autistic women and were significantly correlated with autistic traits in neurotypical women. The findings have important implications for raising awareness in autistic women of the possibility of medical conditions which might need medical attention. In addition, healthcare providers should consider these associations when performing healthcare maintenance checks and/or screening for autism

Sex differences in human perinatal development and autism

Autism is a neurodevelopmental condition that is more frequently diagnosed in males than females. To explain this, in 2014, the prenatal sex steroid theory was proposed. This extended the fetal testosterone theory, published in 2004. The prenatal sex steroid theory proposes that exposure to higher levels of prenatal sex steroids (e.g., prenatal androgens and estrogens) that are on average higher in male fetuses are associated with higher likelihood for autism and elevated autistic traits. This background literature is reported in Chapter 1. In this thesis, eight novel studies are reported that test and extend the prenatal sex steroid theory by investigating perinatal factors related to sex differences in physiology. Study 1 (described in Chapter 2) reports a case-control analysis of steroid levels in the amniotic fluid of males who were later diagnosed as autistic, linked with the Danish Biobank (n = 98 cases, n = 177 controls). This included univariate analyses of both prenatal androgens and estrogens, as well as the aromatisation ratio. All estrogens, but not testosterone, on average were elevated in autistic males. Study 2 (described in Chapter 3) reports a prospective cohort study (the Cambridge Ultrasound and Pregnancy [CUSP] study) of pregnant women and their infants in Cambridge (n=219), who were assessed for their autistic traits during pregnancy and late infancy. Steroid hormone levels were assessed in maternal serum. Estradiol levels correlated with both maternal autistic traits and the male infants’ autistic traits, but there was no correlation with female infants’ autistic traits. Study 3 (described in Chapter 4) reports a large prospective cohort study in Rotterdam (Generation-R) that studied the levels of placental function markers in maternal serum (n=3469), their sex differences in the general population, their association with both autistic traits in childhood (assessed using the Social Responsiveness Scale - SRS), and with likelihood for autism in males. Male-like patterns in placental angiogenic markers, high placental growth factor (PlGF) and low soluble fms-like tyrosine kinase-1 (sFlt-1) levels, respectively correlated with higher autistic traits in females and an autism diagnosis in males. Chapter 5 describes Studies 4, 5, and 6, all based on a longitudinal cohort, the Cambridge Human Infant Longitudinal Development [CHILD] Study. This included prenatal (n=41) and postnatal (n=27) brain MRI imaging and salivary testosterone measurements during mini-puberty. Study 4 found that both male and female infants experienced transient increases in testosterone postnatally (2 to 6 months), but this did not correlate to their autistic traits at 18 months. Study 5 focused on total brain volume and surface area in infancy, as well as rate of brain growth perinatally, all of which correlated negatively with the infant’s autistic traits. Study 6 found that this was driven by low volume in regions that show sex differences and are involved in face recognition. Chapter 6 describes two genetic studies, which found that autism-related genetic variance (rare and common variance respectively) overlaps with X-linked genes that show sex differences in the placenta (Study 7) and correlates with the genetics for early age of menarche (Study 8). Chapter 7 brings all of the findings from Studies 1 to 8 together to draw conclusions and consider limitations and future directions. Based on these analyses, I then propose a new theory on the role of the placenta in mediating sex differences in human perinatal development and autism

Sex differences in placenta-derived markers and later autistic traits in children

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean= 13.5[SD=2.0] weeks gestation) and 2nd trimesters (mean=20.6[SD=1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n=64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, compared to female pregnancies. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2nd: n=3469,b=0.24[SE=0.11], p=0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd: n=3469, ACME: b=0.006, [SE=0.002], p=0.004). In conclusion, higher PlGF levels in the 2nd trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population

Maternal Steroid Levels and the Autistic Traits of the Mother and Infant

Background: Elevated prenatal sex steroids and maternal conditions that are related to sex steroids (e.g., polycystic ovary syndrome) have been positively associated with autism likelihood. It is unclear if this is detectable in the maternal circulation, if it relates to maternal autistic traits, and whether it is also predictive of autistic traits in infants. Methods: : Maternal serum samples were collected as part of routine prenatal screening from pregnant women taking part in the longitudinal Cambridge Ultrasound Siblings and Parents (CUSP) study (n=219) (gestational age: mean=12.7 [SD=0.8] weeks). Concentrations of the following were measured via immunoassays: testosterone (T), estradiol (E2), dehydroepiandrosterone sulphate (DHEAS), progesterone (P); sex hormone-binding globulin (SHBG). Human choriogonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) were collected from clinical records corresponding to the same serum samples. Participants completed the adult Autism Spectrum Quotient (AQ). Infants were followed-up with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) between 18-20 months old (mean=570 days, SD=21.3 days). Results: : Maternal AQ scores significantly correlated with circulating levels of total E2 (Pearson’s r=0.20, p=0.036) and the bioactive fraction of E2 (Pearson’s r=0.26, p=0.008) in univariate and multiple regression models. Total E2, DHEAS and a steroidogenic factor (derived from total E2, DHEAS and T) were all associated with Q-CHAT scores in multiple regression models that controlled for covariates and for an interaction with infant sex. This interaction also had a significant effect, leading to a positive correlation between hormone levels and Q-CHAT scores in males but not in females (interaction term: semipartial correlation r=0.23, p=0.018). The opposite was found for standardised hCG values and Q-CHAT scores, with a positive association in females but not in males (interaction term: semipartial correlation r=-0.22, p=0.009). Limitations: This longitudinal clinical study was relatively small and statistical power was further reduced by the need to account for different effects according to sex. The findings will need to be confirmed in a larger cohort and with clinically diagnosed cases of autism. Conclusion: In line with previous findings, this study’s results suggest that increased steroid synthesis prenatally is related to autistic traits and that this is detectable in the maternal circulation

Is the association between mothers’ autistic traits and childhood autistic traits moderated by maternal pre-pregnancy Body Mass Index?

Background: Previous studies showed that there is a positive association between mothers’ and children’s autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). Method: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient (AQ), and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale (SRS) in Generation R (M = 13.5 years), and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). Result: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; β = 0.20, p < 0.01), in early childhood (Generation R; β = 0.19, p < 0.01), and in early adolescence (Generation R; β = 0.16, p < 0.01). Maternal pre-pregnancy BMI were associated to child autistic traits in Generation R (β = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI for the association between autistic traits of mothers and children both in the Generation R cohort and in the CUSP cohort. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. Conclusion: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed