Abstract
Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen's d=0.37, P=0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism.
Highlights
Autism is characterized by early developmental difficulties in social interaction and communication, alongside highly repetitive stereotyped behavior and/or restricted interests
Given their capacity to exert epigenetic fetal programming influence during early critical periods of brain development,[4,5,6,7] steroid hormones are well-positioned as an important early fetal environmental factor that may interact with other risk factors for autism and other atypical neurodevelopmental conditions that asymmetrically affect the sexes.[2,8,9,10,11]
Ruling out storage time as a possible confound, we found that groups did not differ in terms how long samples were kept in storage
Summary
Autism is characterized by early developmental difficulties in social interaction and communication, alongside highly repetitive stereotyped behavior and/or restricted interests It affects approximately 1% of the population, and males are diagnosed more often than females.[1] While changing diagnostic practice over time and other social variables likely partly contribute to this male bias, biological factors related to the sex chromosomes and/ or fetal sex steroids may have important roles.[2,3] Given their capacity to exert epigenetic fetal programming influence during early critical periods of brain development,[4,5,6,7] steroid hormones are well-positioned as an important early fetal environmental factor that may interact with other risk factors for autism and other atypical neurodevelopmental conditions that asymmetrically affect the sexes.[2,8,9,10,11]. Given prior work,[2,3] we predicted there would be elevated levels of steroidogenic activity across all subgroups on the autism spectrum and across all Δ4 sex steroid hormones, but predicted no difference in cortisol levels
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