Overlap of autism and conditions associated with atypical sex hormone levels or response: A systematic review and meta-analysis

Background: This review explored any altered risk of Autism Spectrum Disorder (ASD) associated with conditions with a known or postulated atypical exposure to androgens and oestrogens in early fetal development, and conditions associated with atypical hormone levels and responses within an individual. Method: Searches of Ovid Medline, PsychInfo and PubMed were completed until November 2019 with inclusion criteria of cohort, case control or clinical studies exploring the overlap of ASD with hormone-related conditions. Results: Of 2640 studies, 49 met inclusion criteria exploring: Polycystic ovarian syndrome (PCOS), Klinefelter Syndrome, Turner Syndrome, Congenital Adrenal Hyperplasia (CAH), cryptorchidism, hypospadias, hirsutism; ovarian, uterine, testicular, cervical cancer; hypergonadotropic hypogonadism. Half had low risk of bias, with confidence in findings ranging from Very Low to Moderate, with all studies observational. Meta-analyses indicated 5 of 23 analyses had significant associations; with significantly increased odds of ASD in women with PCOS 1.48 [95 % CI 1.21–1.80], ASD in offspring of mothers with PCOS 1.53 [95 % CI 1.37–1.72]; but no increased odds of ASD in women with CAH, hirsutism or cancer. In conditions associated with reduced androgens, meta-analyses found an unexpected increased odds of ASD in hypospadias 1.38 [95 % CI 1.07–1.77], cryptorchidism 1.38 [95 % CI 1.11–1.71], and Klinefelter syndrome 6.39 [95 % CI 4.21–9.71]. Conclusion: The androgen hypothesis was supported by 2 of 25 outcomes with 4 outcomes having opposite findings. Other complex factors are likely involved including genetic influences which may override simple sex hormone associations, as well as confounding pregnancy and birth factors inflating associations in some conditions.