Sex ratio of siblings of children diagnosed with autism spectrum disorder

In this issue of DMCN, Mouridsen et al. report that children diagnosed with autism spectrum disorder (ASD) have a highly significant excess of brothers. Here I try to assess this finding in the context of three hypotheses. I have previously summarized the evidence that parental hormone levels around the time of conception correlate with the sex ratio (proportion male) of the resulting offspring.Ex hypothesis, high levels of testosterone (in either parent) are associated with the production of males. Baron-Cohen et al. hypothesized that children diagnosed with ASD were exposed to high intrauterine testosterone levels. As female testosterone levels remain fairly stable across time, it would follow that (if Baron-Cohen’s and my hypotheses were both correct) children with autism should have a statistical excess of brothers. The finding of Mouridsen et al. confirms an earlier finding of a highly significant excess of brothers among the pooled samples of siblings of children with several categories of malebiased neurodevelopmental disorder. So, taken together, these data may be interpreted as supporting the hypothesis of Baron-Cohen et al. The question arises: are there other determinants of ASD? In particular, do the established high postnatal testosterone levels in individuals with autism play any role in the disorder? Grounds for this suspicion will now be outlined. Manning’s finger-length ratio is defined as R=2D ⁄ 4D where 2D is the length of the second digit, and 4D the length of the 4th digit. There is good evidence that R correlates (negatively) with prenatal testosterone. It was originally reported that R also correlates negatively with male adult testosterone level. It may be acknowledged that the meta-analysis of Honekopp et al. failed to confirm this, but evidence will now be given that casts some doubt on this conclusion. R is reportedly strikingly and significantly low in patients with autism, their parents and other relatives. This was interpreted as evidence for the involvement of prenatal testosterone by these authors. But it may be interpreted as evidence also for involvement of postnatal testosterone. Two grounds will now be given for this suggestion. (1) It was hypothesized that R should correlate with offspring sex ratio and this was confirmed. Yet what could have been the mechanism by which this confirmation was accomplished? All the data relating parental hormone levels to corresponding offspring sex ratio seem satisfactorily explained by invoking postnatal hormone levels– not prenatal hormone levels. The latter may plausibly be supposed to programme the brain (as in neurodevelopmental pathologies or in athletic skills). But it seems implausible to suggest that prenatal hormone levels are also directly responsible for offspring sex ratio. I suggest that, if confirmed, the relationship between parental R and offspring sex ratio is mediated by adult hormone levels. (2) It is established that patients with ASD have high androgen levels. Geier and Geier wrote: ‘A review of therapies that have significantly improved outcome in ASD patients (suggest) that they . lower androgens. ’ This suggests that high concentrations of postnatal testosterone, as well as prenatal testosterone, play a causal role in ASD. Science is being advanced here by the awkward progress of three hypotheses which are logically tethered to one another. Research should now be initiated to discover whether postnatal testosterone levels are causally involved in ASD. Settling that point will have repercussions not only for Baron-Cohen’s hypothesis, but for mine and Manning’s.