Background
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by difficulties in social communication and interaction and restricted, repetitive patterns of behavior, interests, or activities [
1]. Previous studies have shown that the prevalence ratio for ASDs is four times greater in men than in women [
2,
3]. Based on such sex-biased prevalence ratios, a number of studies have investigated men-specific hormonal or genetic candidates for ASD risk factors [
3‐
5]. However, the etiology of ASDs in women is largely unknown.
Baron-Cohen and colleagues proposed the extreme male brain (EMB) theory, in which the activities of sex hormones such as testosterone and estrogen during the prenatal period is one of the risk factors for ASDs [
6‐
9]. In typically developing (TD) individuals, male fetuses are exposed to at least 2.5-fold higher levels of testosterone than female fetuses between weeks 8 and 24 of gestation [
10]. This androgen exposure is thought to masculinize cognition, resulting in higher systemizing ability (i.e., understanding things as systems in terms of rules) and lower empathizing ability (i.e., understanding and responding to the mental states of others) [
6‐
9]. Based on this hypothesis, excessive fetal testosterone exposure in men with ASDs causes “extreme male” cognition (superior systemizing and poorer empathizing) relative to TD men [
6‐
9]. Indeed, a recent study demonstrated that testosterone levels in the amniotic fluid samples of mothers of male babies later diagnosed with ASDs were elevated relative to those of TD male babies [
11]. However, it is unknown whether women with ASDs were exposed to high testosterone levels in utero.
Although measurement of amniotic fluid can be used to directly assess prenatal sex hormone exposure, the low prevalence of ASDs in women would require a large cohort study. As an alternative indirect measure, the ratio of the second to fourth digit length (2D:4D) is frequently used to estimate prenatal sex hormone activity. The ratio is affected by both the amount of sex hormone exposure and sex hormone sensitivity [
12‐
15]. Lutchmaya et al. showed that the 2D:4D ratio of the right hand was negatively correlated with the ratio of testosterone to estrogen in amniotic fluid, indicating that individuals exposed to a higher testosterone:estrogen ratio tend to have lower 2D:4D ratios [
12]. A mouse study also demonstrated that inactivation of androgen or estrogen receptors leads to higher or lower 2D:4D ratios, respectively [
15]. If high testosterone activity (especially relative to estrogen) is a risk factor for both sexes, both men and women with ASDs should have lower 2D:4D ratios.
In support of the EMB theory, recent meta-analyses of 2D:4D ratios in subjects with ASDs have suggested that ratios are lower in individuals with ASDs compared to TD individuals [
16,
17]. However, there were few women with ASDs, if any, in most of the investigations [
18‐
27]. Thus, the 2D:4D ratios in women with ASDs were not sufficiently examined in previous studies. Only two studies examining 2D:4D ratios have involved large numbers of women with ASDs (>10) [
28,
29], and neither reported a significant difference in the 2D:4D ratios between women with ASDs and TD women [
28,
29], suggesting that prenatal sex hormone activity is not a risk factor for women with ASDs.
However, previous studies have shown that the prevalence ratio for ASDs differs among different races/ethnicities (e.g., the increased risk for ethnic blacks [
30,
31]). One possible cause for variable prevalence ratios is different levels of prenatal sex hormone activity among races. For instance, an American study of TD individuals reported higher testosterone levels in the amniotic fluid of black women relative to white women [
32]. Another group measured higher testosterone levels in the umbilical cord blood of Asian babies in China compared to Caucasian babies in the USA [
33]. Furthermore, race differences have also been observed in 2D:4D ratio values [
34‐
36] and its relationships with other indices such as sexual orientation [
37] or number of children [
34]. These findings indicate that prenatal sex hormone activity could be a risk factor for ASDs in women of races exposed to higher testosterone in utero, such as Asian or African women. Notably, the two previous studies examining 2D:4D ratios in women with ASDs only assessed Caucasian women (Swedish or Dutch) [
28,
29].
Here, we examined the 2D:4D ratios of women and men with ASDs and TD. We hypothesized that if a higher level of prenatal testosterone activity were a risk factor for ASDs in both sexes, both women and men with ASDs should have lower 2D:4D ratios relative to their TD counterparts. We also examined the relationships between the 2D:4D ratio and individual autistic traits as measured using the autism-spectrum quotient (AQ) [
38] for each group.
Conclusions
In the present study, we found that right 2D:4D ratios were lower in Japanese men with ASDs compared to TD Japanese men. Conversely, Japanese women with ASDs exhibited higher right 2D:4D ratios than TD Japanese women. It has been proposed that high prenatal testosterone leads to lower 2D:4D ratio; however, a recent animal study showed that testosterone injections given to dams induced higher right 2D:4D ratios, especially for female offspring. Therefore, the results of the present study suggest that high prenatal testosterone could be a risk factor both for Japanese men and women with ASDs, elucidating one potential etiology of ASDs in women.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
YaM performed the measurement of digit length and statistical analysis and drafted the manuscript. YO conceived of the study, acquired the data, performed the statistical analysis, and drafted the manuscript. KI conceived of the study and acquired the data. YuM, TF, and YW helped to draft the manuscript. HK conceived of the study and helped to draft the manuscript. All authors read and approved the final manuscript.