https://doi.org/10.1177/1073858420952046 The Neuroscientist 1–18 © The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1073858420952046 journals.sagepub.com/home/nro Review Introduction The physicist, writer, and musician Peter Pesic has lik- ened science to a game of hide and seek, a labyrinth in which the truth is obscured from facile discovery (Pesic 2000). This analogy is particularly apt with regard to research on the etiology of autism spectrum disorder (ASD), experimental evidence pointing to numerous potential contributing factors, but without a clear under- standing of how these factors may interact to result in the symptoms observed. In this review, we briefly summarize the principal hypothetical mechanisms that have been put forward as contributors to the development of ASD, then present a conceptual framework that may help to under- stand how these mechanisms may converge to affect the development of the brain. Incidence and Characteristics of ASD ASD is a complex neurodevelopmental disorder, charac- terized by deficits in the two domains of social communi- cation and restricted, repetitive behaviors or interests (American Psychiatric Association, 2013). It is referred to as a “spectrum” disorder, because there is wide varia- tion in the type and severity of symptoms. Diagnoses of ASD have risen to between 1 in 40 and 1 in 68 children (Christensen and others 2018; Xu and others 2018) com- pared with an estimated incidence of approximately 1 in 150 children in 1992-1994 (Centers for Disease Control and Prevention 2019). The reason for this apparent increase is not entirely clear, but it may, in part, reflect changes in and/or refinement of the diagnostic criteria, as well as increasing efforts to ensure correct diagnosis at an early age when treatment is most effective (Myers and others 2019). 952046NRO XX X 10.1177/1073858420952046The NeuroscientistWilson et al. review-article 2020 1 Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada 2 Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada 3 Departments of Child & Adolescent Psychiatry, Neuroscience & Physiology, and Psychiatry, New York University Langone Health, New York, NY, USA 4 Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA 5 Department of Psychology, University of Guelph, Guelph, Ontario, Canada Corresponding Author: Neil J. MacLusky, Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road, Guelph, Ontario, N1G 2W1, Canada. Email: nmaclusk@uoguelph.ca Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder Hayley A. Wilson 1,2 , Carolyn Creighton 1 , Helen Scharfman 3,4 , Elena Choleris 5 , and Neil J. MacLusky 1 Abstract Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders that affects males more frequently than females. Numerous genetic and environmental risk factors have been suggested to contribute to the development of ASD. However, no one factor can adequately explain either the frequency of the disorder or the male bias in its prevalence. Gonadal, thyroid, and glucocorticoid hormones all contribute to normal development of the brain, hence perturbations in either their patterns of secretion or their actions may constitute risk factors for ASD. Environmental factors may contribute to ASD etiology by influencing the development of neuroendocrine and neuroimmune systems during early life. Emerging evidence suggests that the placenta may be particularly important as a mediator of the actions of environmental and endocrine risk factors on the developing brain, with the male being particularly sensitive to these effects. Understanding how various risk factors integrate to influence neural development may facilitate a clearer understanding of the etiology of ASD. Keywords autism spectrum disorder, sex differences, androgen, neuroinflammation, stress, thyroid hormone