Sex differences in human perinatal development and autism

Abstract

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.