Elevated amniotic fluid steroid hormones and autism risk

"These results provide the first direct evidence of elevated fetal steroidogenic activity in autism". Such were the sentiments of the paper by Simon Baron-Cohen and colleagues [1] (open-access) looking at amniotic fluid samples for the presence of various sex steroid levels: Progesterone, 17α-Hydroxy-progesterone, Androstenedione, Testosterone and Cortisol. Most compounds are found in the Δ4 pathway. Suffice to say that the media kinda liked the press release for this study (see here) and the study findings have been reported by quite a few outlets (see here and see here).

The paper is open-access but as always, I'd like to give a brief overview:

• Based on amniotic samples collected in Denmark (yet again those Scandinavian registries are proving their scientific worth), "all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128)" were compared with 217 asymptomatic controls. Note the focus on males only.
• Samples were in storage for quite a few years (average of 14 years) but were eventually thawed and prepared for analysis by a favourite technique of mine: liquid chromatography tandem mass spectrometry. If you're really interested, the mass spec used was a triple quadrupole system operated in positive ion mode relying on chemical ionisation.
• Results: rather than any one of the sex steroids being singled out as a biomarker for the autism samples, "a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol". Further: "This observation suggests dysregulation of pathways mediated by cytochrome P450-containing enzymes that catalyze the conversion of hormones along the Δ4 and glucocorticoid pathways". One of the figures included in the paper provides a good overview on the extent of the group elevations noted in the study (see here).
• "The source of elevated steroidogenic activity in the fetal development of autism was not tested in the current study, and more research will be needed to understand how different sources such as the fetus, mother, placenta or other environmental factors might contribute to such elevations". In other words, researchers were only recording sex steroid values in samples not looking at the hows and whys of such elevations.

Those who are familiar with the autism research scene will probably know about Prof SBC and his work going back some years (see here). In more recent times, I note that quite a bit more of his work is focusing on the sex hormones and how they may relate to cognitive phenotypes such as systemisers and empathisers (see here and see here) potentially overlapping with facets of the autism and other spectrums. Perhaps more interesting to me has been some shift away from grand sweeping psychological theories of autism to other disciplines pertinent to autism research such as those similar to his analytical chemistry work shown in this post [2]. 

I note in the current paper mention of the words "epigenetic fetal programming" as being one suggestion for how being 'bathed' in elevated levels of these 'male' hormones might potentially explain why a child goes on to develop autism. I know this is a trendy area to talk about these days; David Barker (RIP) must be casting a smile over how far and wide his writings are now seemingly reaching. That being said, I'd be interested to see how subsequent research fares in this area particularly when taking into account other placental-related autism findings and the rise and rise of epigenetics in autism research (see here). The authors also for example write: "The current results may also be relevant to the literature on prenatal stress and autism. We found that cortisol, a biomarker typically associated with stress, is elevated early in the fetal development of autism". Knowing what we think we know about cortisol and autism (see here) again, it will be interesting to see where this research leads. Interestingly too, the authors also talk about GABA and cytokines in their discussion of results hinting at the multitude of possible effects that may stem from their findings.

Finally, I note the authors do add quite a big caveat to their findings: "From a clinical standpoint, the current results say nothing about the potential for such data as a prospective prenatal test of autism risk". This based on an issue that Prof SBC has talked about before in the lay arena (see here) which heads down a potentially quite uncomfortable path. Treading carefully, I await replication of these results and that all-important focus on the hows and whys of elevated foetal steroidogenic activity potentially associated with elevated autism risk.

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[1] Baron-Cohen S. et al. Elevated fetal steroidogenic activity in autism.  Molecular Psychiatry. 2014. June 3.

[2] Steeb H. et al. Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. Mol Autism. 2014 Jan 27;5(1):4.

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Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., Hougaard, D., Abdallah, M., Melgaard, L., Cohen, A., Chakrabarti, B., Ruta, L., & Lombardo, M. (2014). Elevated fetal steroidogenic activity in autism Molecular Psychiatry DOI: 10.1038/mp.2014.48