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Males are three times more likely than females to have autism. Although autism is strongly heritable, the male prevalence of autism must be due to more than just genes since autistic girls carry a much higher mutational load than autistic boys. Thus, having genes for autism alone does not explain why more boys are diagnosed with autism than girls.
The latest evidence suggests that the neurobiological mechanisms of sexual differentiation predispose males to the development of autism. There are numerous reasons to support this conclusion: Autistic women have atypical brain structure in sexually dimorphic regions; the brain of males with autism shows both hypermasculine and hyperfeminine patterns of connectivity; autistics show masculinized scores on sexually dimorphic psychological traits; autistic women have elevated androstenedione levels, the precursor to testosterone; and finally, autistic children have hypermasculine facial features.
While prenatal androgens are responsible for masculinization in humans, prenatal estrogens contribute significantly more to fetal and neonatal brain development. Prenatal estrogens are also critical for the development of one particularly important neurotransmitter system in the cortex, GABA. GABA is one of the brain’s most prevalent neurotransmitters and plays a critical role in neuroplasticity. Estrogens support the normal development of the cortex by influencing GABA activity while inducing synapse formation and neuronal differentiation; these functions are all atypical in the autistic brain.
This latest study measured prenatal levels of estriol, estradiol, estrone, and estrone sulphate in the amniotic fluid of boys with and without autism. They provide the first evidence that elevated levels of prenatal amniotic estradiol, estriol, and estrone are each associated with autism, with estradiol levels being the most significant predictor of autism in males.
The authors speculated that these hormonal changes in the uterine environment could potentially be attributed to changes within the placenta. This is a reasonable hypothesis given that the placenta acts as an endocrine regulator at the maternal-fetal interface. The placenta is also the main source of estrogen production for the fetus. This suggestion is consistent with other lines of evidence that suggest a causal role for the placenta in the etiology of autism. First of all, there is increased placental inflammation in autism. Studies from my lab have previously demonstrated that the brains of autistics also have elevated levels of inflammatory proteins. Second, the morphology of the placenta is atypical and of increased size. Third, complications related to placenta hypertensive disorders are more frequent in pregnancies that result in autism. Previous studies have shown that placental dysfunction disproportionately affects males more than females.
The results of this novel study demonstrate for the first time that prenatal estrogens contribute to the probability of developing autism and offer the best current explanation for the prevalence of autism in males. The elevated prenatal steroidogenic activity likely further affects sexual differentiation, brain development, and function that are characteristic of this disorder.
References
Baron-Cohen S, et al (2020) Foetal oestrogens and autism. Molecular Psychiatry Vol 25:2970–2978. https://doi.org/10.1038/s41380-019-0454-9
