Sex Differences in Autism Spectrum Disorder: a Review

Abstract

Purpose of review: Neurodevelopmental disorders disproportionately affect males. The mechanisms underlying male vulnerability or female protection are not known and remain understudied. Determining the processes involved is crucial to understanding the etiology and advancing treatment of neurodevelopmental disorders. Here, we review current findings and theories that contribute to male preponderance of neurodevelopmental disorders, with a focus on autism.

Recent findings: Recent work on the biological basis of the male preponderance of autism and other neurodevelopmental disorders includes discussion of a higher genetic burden in females and sex-specific gene mutations or epigenetic changes that differentially confer risk to males or protection to females. Other mechanisms discussed are sex chromosome and sex hormone involvement. Specifically, fetal testosterone is involved in many aspects of development and may interact with neurotransmitter, neuropeptide, or immune pathways to contribute to male vulnerability. Finally, the possibilities of female underdiagnosis and a multi-hit hypothesis are discussed. This review highlights current theories of male bias in developmental disorders. Topics include environmental, genetic, and epigenetic mechanisms; theories of sex chromosomes, hormones, neuroendocrine, and immune function; underdiagnosis of females; and a multi-hit hypothesis.

Keywords: Autism; Extreme male brain theory; Female protective effect; Fetal testosterone; Neurodevelopmental disorders; Sex differences.

Figure 1.

Sex chromosomes (XX=female; XY=male) determine which gonads will form and which sex hormones (mainly testosterone, estradiol, and progesterone) they will produce. Fetal testosterone is important for permanent masculinization of the male brain and body during the organizational period (late gestation/birth, in rodents). This is the proposed period for vulnerability to ND. Sex hormones then surge during the activational period (puberty) for more transient effects; males have relatively stable testosterone levels, and females have variable hormone levels over the 4–5 day estrous cycle. Modified from [54].

Figure 2.

Summary of theories and phenomena that contribute to the male bias of ASD and ND. fT = fetal testosterone, SNP = single nucleotide polymorphism, SNV = single nucleotide variant, CNV = copy number variant, MeCP2 = methyl-CpG-binding protein 2, VPA = valproic acid.