Congenital Abnormalities of the Male Reproductive System and Risk of Autism Spectrum Disorders

Ran S. Rotem; Gabriel Chodick; Michael Davidovitch; Russ Hauser; Brent A. Coull; Marc G. Weisskopf

Disclosures

Am J Epidemiol. 2018;187(4):656-663. 

In This Article

Abstract and Introduction

Abstract

Androgens have an extensive influence on brain development in regions of the brain that are relevant for autism spectrum disorder (ASD), yet their etiological involvement remains unclear. Hypospadias (abnormal positioning of the urethral opening) and cryptorchidism (undescended testes) are 2 relatively common male birth defects that are strongly associated with prenatal androgen deficiencies. Having either disorder is a proxy indicator of atypical gestational androgen exposure, yet the association between these disorders and autism has not been extensively studied. We analyzed male singleton live births (n = 224,598) occurring from January 1, 1999, through December 31, 2013, in a large Israeli health-care organization. Boys with autism, cryptorchidism, and hypospadias were identified via International Classification of Diseases, Ninth Revision, codes, with further verification of autism case status by review of medical records. In multivariable-adjusted analyses, the odds ratio for ASD among boys with either condition was 1.62 (95% confidence interval (CI): 1.44, 1.82). The odds ratio for boys with cryptorchidism only was 1.55 (95% CI: 1.34, 1.78), and that for boys with hypospadias only was 1.65 (95% CI: 1.38, 1.98). ASD risk was not elevated among unaffected brothers of hypospadias or cryptorchidism cases, despite familial aggregation of all 3 conditions, providing some indication for the possibility of pregnancy-specific risk factors driving the observed associations. Results suggest that in-utero hypoandrogenicity could play a role in ASD etiology.

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing prevalence worldwide.[1] While genetics play a strong role in its etiology, evidence is increasing that environmental exposures also affect ASD risk.[2–7] Androgens are known to affect fetal brain development, and a role for androgens in ASD etiology has been specifically proposed based on the participation of sex hormones in the regulation of neural domains involved in communication and social interaction that are relevant for ASD, as well as more indirectly based on the involvement of several genes that regulate sex hormone pathways in ASD pathogenesis.[8–11] Thus, a better understanding of the contribution of in-utero androgen exposure in ASD etiology could have tremendous implications, both for understanding ASD etiology and for potentially generating interventions to reduce its burden.

Androgens also play pivotal roles in the development of the urethra and external genitalia in males. Androgen deficiency leads to the development of cryptorchidism (undescended testis) and hypospadias (abnormal positioning of the urethral opening on the ventral side of the penis),[12–14] two of the most common birth defects in newborn boys. An increasing prevalence of these anomalies has been reported over the past several decades.[15,16] Intriguingly, a correlation between county-level rates of male reproductive tract disorders and ASD has been observed ecologically,[17] but to date this was only explored on an individual level in 1 study, and those investigators only considered the less common hypospadias, not cryptorchidism.[18] Thus, to further examine the association between androgen-dependent male reproductive system abnormalities and ASD, we explored the association between hypospadias and cryptorchidism and a clinical diagnosis of ASD in a large birth cohort in Israel.

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