Neurodevelopmental Consequences of Fetal Androgen Exposure Depend on Sex

Background: Autism spectrum disorder (ASD) displays a striking sex bias, which has fueled research around the hypothesis that aberrant sex hormone exposure may be a contributing factor to the condition. Previous studies utilized morphological features that are known to reflect androgen exposure – e.g. digit ratio or facial features – to explore the biological mechanisms behind ASD. However, few studies have compared these measures to the specific traits prevalent in the disorder. Even fewer have broadened their sample to include not only individuals with ASD, but also typically developing individuals and those with other neurodevelopmental conditions such as language impairment or intellectual disability. With a diagnostically diverse cohort, determining the influence of prenatal androgen exposure on clinically relevant traits will further our understanding of the role of sex in neurodevelopment.

Objectives:  This study investigated the relationship between prenatal androgen exposure and behavioral traits that exist to varying degrees in the general population but are particularly pronounced in individuals diagnosed with ASD.

Methods:  642 individuals spanning a spectrum of social, behavioral, communication, and cognitive capabilities were recruited from hospitals and clinics across the state of Iowa. Two morphological features – digit ratio and facial masculinity – were used as proxy measures for prenatal androgen exposure. 2D:4D ratios were calculated from finger length measures obtained from subjects’ hand scans; facial masculinity was determined through computational analyses of subjects’ photographs. Self- and parent-reports were corroborated by examination of medical records to determine medical history and comorbidities. Scores for ‘Social Deficit’, ‘Sensory Sensitivity’, ‘Restricted/Repetitive Behaviors’, ‘Anger/Aggression’, and ‘Cognitive Deficit’ were calculated from these responses.

Results: The two morphological features used to reflect prenatal androgen exposure – 2D:4D ratio and facial masculinity – were significantly correlated. Both measures were associated with ASD-related characteristics, in a sex-dependent manner. In male subjects, greater prenatal androgen exposure correlated with fewer restricted/repetitive behaviors, lower aggression, fewer sensory sensitivities, and less severe cognitive deficits. In female subjects, greater prenatal androgen exposure resulted in more severe behaviors and deficits. Overall, neurodevelopmental symptomatology was more severe when prenatal androgen exposure was discordant with biological sex.

Conclusions: The influence of prenatal androgen exposure on ASD-related behaviors, social abilities, and cognitive deficits is mediated by sex. These effects are not limited to individuals with ASD or other neurodevelopmental conditions, as they were detectable in both clinical and subclinical populations.