Saturday, May 19, 2012

Validating the Extreme Male Brain Theory of Autism

According to an abstract published for IMFAR 2012, it looks like Simon Baron-Cohen has finally gotten around to actually testing the core idea of his extreme male brain theory of autism.  The core idea being that children who go on to develop autism are exposed to a higher than normal level of prenatal testosterone.

To do so, the good doctor actually measured the level of four sex hormones (progesterone, 17a-hydroxyprogesterone, androstenedione, and testosterone) and cortisol in the amniotic fluid of 62 males with autism and 231 males without autism that had been preserved as part of the Danish Historic Birth Cohort.

The results of this analysis, although preliminary, are quite surprising.  The autism group did show an increased level of testosterone, that much was predicted by the theory.  But what was not expected was that the autism group also showed an increased level of the other three sex hormones as well.  The levels of cortisol were the same between the autism and control groups.

On a trivial level, this result calls into question the core idea of extreme male brain theory of autism because it isn't just testosterone that is out of balance, it is other sex hormones as well (i.e. testosterone and estrogen would likely both be out of balance).

On a non-trivial level, this result shows that far more than just sex hormones are out of balance.  These four  hormones are involved in other biological processes as well.  Wikipedia has a nice picture of how these hormones fit together -

The biology is a little beyond me, but notice cortisol hanging out on the right side of the picture?  I have to wonder how you can push several parts of the process without impacting one of the end results of the pathway.

Regardless, from what I understand, these four hormones are tied to the CYP17A1 pathway and this pathway is involved in a whole lot of other things.  These things include the oxidation of organic substances, metabolism of drugs and other toxic chemicals, and the synthesis of cholesterol, steroids, and other lipids.

Notice anything familiar on that list?  Here a hint, all of these things have been tied to autism or found to be out of balance in some people with autism.

So, what do you think happens to a developing fetus when an important biological pathway like this is pushed out of balance?  I don't understand the biology well enough to fully grasp the consequences but I don't think it can be anything good.

Many of the body's systems are are cross linked and when you push one of them out of balance you are going to unbalance other parts as well.  And if there is one common theme that ties together all of the many abnormal biological findings in autism, it is a tendency to be out of balance and at one extreme or the other.

Of course, these results are preliminary and need to be replicated by other groups.  The findings also need to be replicated in the general autism population.  The current paper, like so many of Simon Baron-Cohen's papers, focuses exclusively on the high functioning males with autism.  It excluded anyone with autism who had intellectual disability and anyone who was female.

These result also beg the question of why all of these hormones are out balance in the first place.  Something has to be pushing these hormones out of balance in either the mother or fetus (and please don't say "it's genetic").  It is a good thing that endocrine disruptors such as Bisphenol A aren't becoming more widespread and aren't being found in high levels in pregnant women or I might be worried.

And, almost without a doubt, the "autistic rights" movement is going to have a conniption about these results.  Instead of focusing on the fact that results like this help us to better understand the biology of autism and to come up with better ways of helping people with autism, I can almost guarantee that they are going to focus on the idea that this result might lead to a prenatal test for autism.

The summary of the paper is available from the IMFAR 2012 site and I am including it below.

S. Baron-Cohen, B. Auyeung1, B. Nørgaard-Pedersen2, D. M. Hougaard2, M. W. Abdallah2,3, L. Melgard2, A. Cohen2, L. Ruta1 and M. V. Lombardo1, (1)Autism Research Centre, University of Cambridge, Cambridge, United Kingdom, (2)Department of Clinical Biochemistry and Immunology, Statens Serum Institute, Copenhagen, Denmark, (3)Department of Epidemiology, Aarhus University Faculty of Health Sciences, Aarhus C, Denmark

Background: Autism Spectrum Conditions (ASC) are much more common in males. One hypothesized biological mechanism that could potentially influence this male bias is fetal testosterone (FT) or more generally the broader steroidogenic pathway leading to the synthesis of testosterone (Baron-Cohen et al 2011, PLOS-Biology; Baron-Cohen et al, 2005, Science). Sex steroids are well established as an epigenetic fetal mechanism for modifying gene expression and a host of other molecular/cellular factors in early brain development and may be helpful as predictive markers for those who may be at increased risk for later diagnosis.

Objectives: To test for the first time the hypothesis that fetal steroidogenic activity is elevated in individuals who later receive a diagnosis of ASC.

Methods: 62 male cases of classic autism (without a comorbid diagnosis of ’mental retardation’) or Asperger Syndrome and 231 typical male controls were selected from the Historic Birth Cohort, a biobank of amniocentesis samples taken from the Danish population since 1993. Using mass spectrometry we assessed the concentration of 4 hormones in the ?4 steroidogenic pathway tied explicitly to CYP17 enzymatic pathway (i.e. progesterone, 17a-hydroxyprogesterone, androstenedione, and testosterone) in amniotic fluid sampled during weeks 10-20 of gestation. Cortisol was also measured as a control hormone that is not within the main ?4 sex steroid biosynthesis pathway. Analysis of the main hypothesis (that ?4 pathway hormones are elevated in ASC) consisted of computing the multivariate Wilk’s lambda statistic within a permutation test (re-computed over 1,000,001 iterations). Further classification analyses were implemented using logistic regression and classification performance measures were compared to null distributions estimated under chance conditions via permutation tests.

Results: A permutation test (1,000,001 iterations) on the multivariate Wilk’s lambda statistic showed that when testing all hormones there was an overall group difference in the direction of ASC>Control (p=0.01). Following up this multivariate result with tests on each hormone individually, we found that concentration of all 4 steroidogenic hormones in the ?4 pathway were elevated in the ASC group, but there was no between-group difference in cortisol concentration. Logistic regression was then used to classify diagnostic status using all hormones. Classification accuracy, specificity, PPV, and NPV were all significantly higher than chance values estimated by permutation tests (all p<0.02). Sensitivity approached statistical significance (p=0.06).

Conclusions: This work represents the first direct verification that fetal exposure to sex steroids is elevated in those who later receive a diagnosis of autism. Given the role of sex steroids in a host of interactions at the genetic and molecular/cellular level, this finding represents an important breakthrough in understanding early factors that contribute to the pathophysiology of ASC. Classification analyses show that while these markers are statistically significant in predicting later diagnosis status, such markers should not be used as a fetal test. Future work comparing autism to other neurodevelopmental conditions will be important in clarifying the specificity of such markers to autism, and how such fetal hormones impact the neurodevelopment of autism.


  1. Interesting...It would also be interesting to see what health issues would cause mum to have hormones out of whack that predispose offspring to autism, such as the pill, undiagnosed celiacs, the crap in our environment, etc.

    1. I would like it if we started finding out just how many mothers have hormonal imbalances or other biological problems such as immune disruption. We need more studies like this one - - but not limited to just autism.

  2. I wonder if they controlled for the differences in life-style and social contacts among the autistics versus the controls that could maybe cause these hormones to go out of whack later in life and not just during fetal development, infancy or shortly afterwards.

    I wonder why the control group was so much larger than the autistic group.

    1. There was a study about a month ago that looked at testosterone in a high functioning adults and found that men had a normal level while women had an elevated level. But the women also showed an increased level of dehydroepiandrosterone sulfate which is involved (in some way) in the pathway pictured above.

      Or in other words, yes, there are some limited signs that the pathway is still unbalanced in adult women with autism.

      As for the size of the groups, I'm not sure. I would guess that they wanted to make sure that levels for the control group were really the normal value instead of just a sampling error.

  3. Well y'know there is some preliminary evidence that endocrine disruptors like phthalates might be implicated in autism as per the recent finding of elevated levels: (full-text)
    It's not proof of anything aside from the fact that a small group of people with autism seem to be better excretors of some of these compounds, but certainly it asks some interesting questions...

    1. Thanks for the link, I hadn't seen that one yet. I have seen a bunch of papers over the years that suggested that endocrine disruptors might play a role in autism but not too many that actually measured results in people with autism.

  4. All human neonates during the first year of life undergo what is known as the 'neonatal testosterone surge' During the surge, increased production of testosterone occurs, higher in males than in females.

    Birth aspyxia is a known autism risk factor. Induced birth aspyxia (global birth hypoxia)in mice produced increased levels of testosterone production during the neonatal testerone surge in male and female mice. Over time the testostorone surge subsides and testosterone production tends to normalize. When normalization occurs measuring testosterone levels in puberty, adolescence and in adults may be uninformative.

    General population studies that apply Baron-Cohen's AQ scores indexed by Apgar scores is warrented. I have a paper under peer review exploring this very topic.


    Boksa P, Zhang Y. (2008). Global birth hypoxia increases the neonatal testosterone surge in the rat. Neuroendocrinology.88(4):266-75.

    Jensen RA (2012). Brief Report: Klinefelter Syndrome and XYY Syndrome: The extreme male brain theory of autism and the role of early testosterone production in brain development and behavior. Under review.

  5. Thanks for this MJ. I'd like to see these kinds of studies go one step further. I'd like to see the mothers of these HFA kids undertake the Broad Autism Phenotype test to see if they exhibit any ASD characteristics.

  6. BAP tests have been conducted in Down syndrome with autism featuring the interplay between a de novo genetic mutation and a background BAP genetic effect that follows a developmental trajectory to an autism diagnosis. Ghaziuddin compared a group of Downs Syndrome individuals and their first degree relatives (parents and siblings) with or without a diagnosis of autism. In Downs Syndrome with autism there was an excess of first degree relatives who met the description of BAP features compared to first degree relatives in Downs Syndrome children without autism who did not. The Downs Syndrome mutation and autism was not present in first degree relatives, parents and siblings, and the genes underlying the BAP component part are independent of and is a background genetic effect acting on the neuroanatomical alterations associated with intellectual disability (ID) in Downs Syndrome ( Ghaziuddin 2000 ) ( Ghaziuddin 1997 ).