Valproate-Induced Autism and Sexual Hormone Disturbances: A Literature Review and Hypotheses

Autism spectrum disorders (ASD) are neurodevelopmental disorders whose aetiology remains obscure. Multiple human and animal studies have shown that prenatal exposure to valproate increases the risk of ASD in children. Although the mechanisms implicated are still poorly understood, several hypotheses have been put forward; one being that the alteration of the prenatal hormonal milieu could be involved. Indeed, hormone disruption was observed in women with epilepsy or bipolar disorder treated with valproate with an increased risk of experiencing hyperandrogenism or an androgen-associated pathology such as polycystic ovary syndrome (PCOS) or diabetes. This could be explained by an inhibition of aromatase, the enzyme responsible for the aromatisation of androgens into oestrogens. Hormone disruption could impair neurodevelopment through the involvement of the orphan retinoic acid receptor alpha (RORA), a nuclear receptor whose expression is regulated by dihydrotestosterone (DHT) as well as estradiol, and whose transcriptional targets are implicated in ASD. Moreover, neuroestradiol is a key regulator of neurodevelopment and the effects of its disruption seem to overlap with the consequences of prenatal exposition to valproate. Finally, the onset of autism seems to be more frequent when pregnancies were affected by conditions hormonal disturbances such as obesity, diabetes, pre eclampsia or prematurity. This provides a better understanding of valproate-induced autism patterns and opens up new avenues of research to better understand the development of this disorder.