Autism, Asperger's and prenatal testosterone

Introduction: why autism studies may shed light on the behavior of the general population

People with autism or Asperger's have been found to have a lower 2D:4D digit ratio than average, and to have been exposed to higher amounts of prenatal testosterone:

"We found that the 2D:4D ratios of children with autism, their siblings, fathers and mothers were lower than population normative values. Children with AS, who share the social and communicative symptoms of autism but have normal or even high IQ, had higher 2D:4D ratios than children with autism but lower ratios than population normative values."

(source: The 2nd to 4th digit ratio and autism, J T Manning PhD, S Baron-Cohen PhD, S Wheelwright MA and G Sanders PhD, Version of Record online: 2 MAR 2007, retrieved July 1st 2016)

"[The study result] suggests that [boys with higher levels of fetal testosterone] have a greater proclivity for "approach-related behaviors," such as fun-seeking and impulsivity. [...] For males, such behaviors are often heightened in teenage years and are found in extremes in many psychiatric conditions, such as [...] autism."

(source: Fetal Testosterone May Program Boys' Behavior, By Live Science Staff | November 5, 2012, retrieved 22/07/2016)

"fT (fetal Testosterone) levels were positively associated with higher scores on the CAST (Childhood Autism Spectrum Test) and AQ-Child (Child Autism Spectrum Quotient). This relationship was seen within sex as well as when the sexes were combined, suggesting this is an effect of fT rather than of sex per se. [...] These findings are consistent with the hypothesis that prenatal androgen exposure is related to children exhibiting more autistic traits."

(source: British Journal of Psychology (2009), 100, 1–22, Fetal testosterone and autistic traits, Bonnie Auyeung, Simon Baron-Cohen, Emma Ashwin, Rebecca Knickmeyer, Kevin Taylor, and Gerald Hackett)

"“We previously knew that elevated prenatal testosterone is associated with slower social and language development, better attention to detail, and more autistic traits. Now, for the first time, we have also shown that these steroid hormones are elevated in children clinically diagnosed with autism. [...] These new results are particularly striking because they are found across all the subgroups on the autism spectrum, for the first time uniting those with Asperger Syndrome, classic autism, or Pervasive Developmental Disorder Not-Otherwise-Specified.”"

(source: Elevated ‘Male Hormones’ During Fetal Development Linked With Autism, www.iflscience.com, retrieved 22/07/2016, referring to Molecular Psychiatry (2015) 20, 369–376; doi:10.1038/mp.2014.48; published online 3 June 2014,Elevated fetal steroidogenic activity in autism, S Baron-Cohen et al.)

"The Empathizing–Systemizing (E-S) theory of typical sex differences suggests that individuals may be classified based on empathy and systemizing. An extension of the E-S theory, the Extreme Male Brain (EMB) theory suggests that autistic people on average have a shift towards a more masculinized brain along the E-S dimensions. Both  theories have been investigated in small sample sizes, limiting their generalizability. Here we leverage two large datasets (discovery n = 671,606, including 36,648 autistic individuals primarily; and validation n = 14,354, including 226 autistic individuals) to investigate 10 predictions of the E-S and the EMB theories. In the discovery dataset, typical females on average showed higher scores on short forms of the Empathy Quotient (EQ) and Sensory Perception Quotient (SPQ), and typical males on average showed higher scores on short forms of the Autism Spectrum Quotient (AQ) and Systemizing Quotient (SQ). Typical sex differences in these measures were attenuated in autistic individuals. Analysis of “brain types” revealed that typical females on average were more likely to be Type E (EQ > SQ) or Extreme Type E and that typical males on average were more likely to be Type S (SQ > EQ) or Extreme Type S. In both datasets, autistic individuals, regardless of their reported sex, on average were “masculinized.” Finally, we demonstrate that D-scores (difference between EQ and SQ) account for 19 times more of the variance in autistic traits (43%) than do other demographic variables including sex. Our results provide robust evidence in support of both the E-S and EMB theories."

(Greenberg, David M., Varun Warrier, Carrie Allison, and Simon Baron-Cohen. "Testing the empathizing–systemizing theory of sex differences and the extreme male brain theory of autism in half a million people." Proceedings of the National Academy of Sciences (2018): 201811032.)

(see also Effects of (fetal) testosterone on brain and behavior)

Inversely, the (neurological) study of people with autism may give indications of how prenatal testosterone influences the human brain in general, also in those who have been exposed to levels lower than those found in persons on the autistic spectrum. Autistic people might be on the extreme end of high prenatal testosterone levels, while a significant portion of non-autistic ("neurotypical") people may exhibit traits which tend towards the autistic extremes (eg. low empathy, agression, systemizing versus empathizing, etc), without actually being so extreme, depending on prenatal testosterone levels.

General studies on autism

"Autistic phenotypes have been linked (...) to increased protein synthesis at synapses (Bourgeron, 2009), higher excitatory to inhibitory neurotransmission (Rubenstein and Merzenich, 2003), enhanced local compared to global processing and connectivity (Happé and Frith, 2006), a bias toward systemizing over empathizing (Baron-Cohen, 2009), and enhanced perceptual functioning (Mottron et al., 2006). These patterns and theories are not mutually exclusive (...)."

(Crespi, Bernard J. "Autism As a Disorder of High Intelligence." Frontiers in Neuroscience 10 (2016).)

Tendency of people with autism to partner with others on the spectrum may raise the condition's prevalence

"The tendency of people with autism to partner with others on the spectrum may raise the condition’s prevalence within families and across the population, according to a new study.

Researchers used genetic modeling to estimate the impact of this ‘nonrandom mating’ pattern among individuals with autism. The approach uses equations to deduce how genetic traits move through populations."

"People with autism are up to 11 times more likely than their typical peers to choose a partner on the spectrum."

(Partner preferences may contribute to autism prevalence, Spectrum, December 5 2016)

People with autism have more symmetrical brains

"[I]n typically developing young people, the right brain hemispheres had densely packed connections.

'This fits with the idea that the right hemisphere has a more integrative function, bringing together many kinds of information,' the team wrote in a summary of their research.

However, in the participants with ASD, these brain connections were more evenly distributed across both hemispheres.
[...]

MRI scans revealed that connections between white matter in the brains of young people with autism were more symmetrical across hemispheres. [...]

'The idea behind asymmetry in the brain is that there is a division of labor between the two hemispheres,' Müller said. 'It appears this division of labor is reduced in people with autism spectrum disorder.'

That lack of specialization could manifest itself in what Müller calls 'weak central coherence' — a concept best summed up in the idiom, 'not seeing the forest for the trees.' Many people with ASD are very good at seeing details but have difficulty putting it all together into a cohesive narrative, he explained."

(Brain Connections Show More Symmetry Between Hemispheres in People With Autism,
Neuroscience News, December 1, 2016)

Facial features of boys with autism and Asperger's

"White lines are statistically significantly increased in boys with autism spectrum disorder (ASD), and black lines are statistically significantly reduced in boys with ASD relative to typically developing (TD) boys."

(source: https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-2-15)



"Frontonasal prominences (FNP) and lateral nasal prominences (LNP) are shown in purple, maxillary prominences (MAX) are shown in blue, mandibular prominences (MAND) are shown in green and second branchial arch derivatives are shown in shades of pink." 

(source: https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-2-15)

"We found that essential autism in boys is associated with a distinctive facial phenotype characterized by an increased breadth of the mouth, orbits and upper face, combined with a flattened nasal bridge and reduced height of the philtrum [the divot below the nose, above the top lip] and maxillary [upper jawbone] region. [...]
[W]e found a narrowing of the intercanthic distance [distance between the inner corners of the eyes], or mild hypotelorism [distance between the eyes]. These findings are complementary in that we found an overall decrease in intercanthic distance, which potentially translates to decreased interpupillary distance, although we did not directly measure that distance.[...]

(source: Facial phenotypes in subgroups of prepubertal boys with autism spectrum disorders are correlated with clinical phenotypes, Kristina Aldridge e.a., Molecular Autism 2011, retrieved July 2nd 2016)

"Aldridge and colleagues found the following distinct differences between facial characteristics of children with autism and those of typically developing children:
Children with autism have a broader upper face, including wider eyes.
Children with autism have a shorter middle region of the face, including the cheeks and nose.
Children with autism have a broader or wider mouth and philtrum -- the divot below the nose, above the top lip."

(source: Autistic facial characteristics identified, ScienceDaily, october 21 2011, retrieved July 2nd 2016)

More Asperger's in maths, physics, engineering and computer science than in general population

"A recent survey of Cambridge undergraduates confirmed the belief that it is among the students of mathematics, physics, engineering and computer science that Asperger syndrome is most likely to be found."

(James, Ioan. "Singular scientists." Journal of the Royal Society of Medicine 96.1 (2003): 36-39.)

Current standard tests for detecting autism may miss autistic females

"Overall, the findings suggest that some autistic females may be missed by current diagnostic procedures."

(Ratto, Allison B., et al. "What About the Girls? Sex-Based Differences in Autistic Traits and Adaptive Skills." Journal of Autism and Developmental Disorders (2017): 1-14.)

Autistic traits are on a continuum in the wider community, with ASD representing an extreme end

"There is accumulating evidence that autistic traits are on a continuum in the wider community, with ASD representing an extreme end of the distribution."

(Tan, Diana Weiting, Murray T. Maybery, Michael W. Clarke, Renata Di Lorenzo, Melissa O. Evans, Michael Mancinone, Christina Panos, and Andrew JO Whitehouse. "No relationship between autistic traits and salivary testosterone concentrations in men from the general population." PloS one 13, no. 6 (2018): e0198779.)

Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy

"Impairments in social responsiveness in offspring, as indexed by SRS total score, significantly increased as a function of the frequency and severity of their mothers’ NVP [Nausea and vomiting during pregnancy], as did the level of language difficulties as indexed by the Global Communication Composite of the CCC-2.
The strong, positive association between increasing frequency and severity of NVP and ASD severity in offspring provides further evidence that exposure to an atypical hormonal environment during prenatal life may affect neurodevelopment and contribute to the ASD phenotype."

(Whitehouse, Andrew JO, Gail A. Alvares, Dominique Cleary, Alexis Harun, Angela Stojanoska, Lauren J. Taylor, Kandice J. Varcin, and Murray Maybery. "Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study." Molecular Autism 9, no. 1 (2018): 37.)

Criticism of the 'extreme male brain' theory as an explanation for autism

"The implication of this critical review of theory is that the concept of ‘the extreme male brain’ as a description or explanation of autism should be abandoned and replaced with the recognition that scores at any point on the AQ can be the product of a brain within either a male of female person. This allows the search for the biological basis, developmental causes and clinical correlates of autism to be broadened beyond that of differences between the sexes."
[...] ‘[E]ssentialism’ is the philosophical position which claims that things have a set of characteristics that makes them what they are. In the current context, essentialism would claim that there is such a thing as ‘maleness’ and that men deviating from this maleness are not truly male, rather than that such variation merely makes maleness more diverse."

(Ridley, Rosalind. "Some difficulties behind the concept of the ‘Extreme male brain’in autism research. A theoretical review." Research in Autism Spectrum Disorders 57 (2019): 19-27.)

Further support for extreme male brain theory concerning autism

"We demonstrated that females and males with ASD tended to follow the male pattern of developmental changes in interhemispheric connectivity, supporting the EMB theory of ASD."

(Kozhemiako, Nataliia, Vasily Vakorin, Adonay S. Nunes, Grace Iarocci, Urs Ribary, and Sam M. Doesburg. "Extreme male developmental trajectories of homotopic brain connectivity in autism." Human Brain Mapping, First published: 11 October 2018.)

High-functioning Autism (Asperger) associated with low 2D:4D in women and high 2D:4D in men

"Abstract
BACKGROUND:
The 'extreme male brain' theory suggests that autism spectrum disorder (ASD) is an extreme variant of male intelligence. However, somewhat paradoxically, many individuals with ASD display androgynous physical features regardless of gender.
AIMS:
To assess physical measures, supposedly related to androgen influence, in adults with and without ASD.
METHOD:
Serum hormone levels, anthropometry, the ratio of 2nd to 4th digit length (2D:4D) and psychiatric symptomatology were measured in 50 adults with high-functioning ASD and age- and gender-matched neurotypical controls. Photographs of face and body, as well as voice recordings, were obtained and assessed with respect to gender coherence, blindly and independently, by eight assessors.
RESULTS:
Women with ASD had higher total and bioactive testosterone levels, less feminine facial features and a larger head circumference than female controls. Men in the ASD group were assessed as having less masculine body characteristics and voice quality, and displayed higher (i.e. less masculine) 2D:4D ratios, but similar testosterone levels to controls. Androgynous facial features correlated strongly and positively with autistic traits measured with the Autism-Spectrum Quotient in the total sample. In males and females with ASD dehydroepiandrosterone sulfate did not decrease with age, in contrast to the control group.
CONCLUSIONS:
Women with ASD had elevated testosterone levels and several masculinised characteristics compared with controls, whereas men with ASD displayed several feminised characteristics. Our findings suggest that ASD, rather than being characterised by masculinisation in both genders, may constitute a gender defiant disorder."

(Bejerot, Susanne, Jonna M. Eriksson, Sabina Bonde, Kjell Carlström, Mats B. Humble, and Elias Eriksson. "The extreme male brain revisited: gender coherence in adults with autism spectrum disorder." The British Journal of Psychiatry 201, no. 2 (2012): 116-123.)

Many different neurological characteristics underly a common diagnosis of ASD

"Growing evidence shows that neural bases of ASDs cannot be pinpointed to specific regions of the brain, but that symptomatology is instead linked to atypical connectivity within and between functionally specialized brain networks (including ‘social brain’ networks). However, few neuroimaging findings have been widely replicated and no clear picture of the brain bases of sociocommunicative impairments in ASDs has emerged.
A main factor that has prevented consensus findings is etiological diversity. While diagnostic criteria focus on social deficits in ASDs, these probably result from the convergence of many different neurodevelopmental trajectories and many different causative factors."

(Müller, Ralph-Axel, and Inna Fishman. "Brain Connectivity and Neuroimaging of Social Networks in Autism." Trends in Cognitive Sciences (2018).)

Autism and neurological "rigidity"

"What does autism look like in the brain?A new study offers a fresh perspective on how autism works in the brain. Symptoms, the authors say, may be linked to persistent connections in the brain."

(What does autism look like in the brain?, Medical News Today, Published Tuesday 20 November 2018 By Maria Cohut, Fact checked by Paula Field)

Autism signs in ears and mouth form

"[M]inor malformations of the external ears -- notably posterior rotation, in which the top of the ear is tilted backward more than 15 degrees, are more common in children with autism than in typically developing children, children with mental retardation or siblings of children with autism. (...)
Child with autism is normal in appearance, at least to the untrained eye. But he has a few physical anomalies characteristic of the disorder. The corners of his mouth are low compared with the center of his upper lip, and the tops of his ears flop over (left). His ears are a bit lower than normal and have an almost square shape (right)."

(The Early Origins of Autism by Patricia M. Rodier, originally published in "Scientific American," February 2000)

Low fetal cortisol associated with ASD

"Fetal exposure to lower levels of maternal cortisol was associated with higher levels of ASD symptoms only among boys. The observed hypocortisolemic profile exhibited by these mothers may indicate a risk factor that precedes the stress of caregiving for a child with ASD and may not be solely a consequence of the stress of caregiving, as previously thought. These findings confirm the value of examining prenatal hormone exposures as predictors of ASD risk and support the premise that altered prenatal steroid exposures may play a role in the etiology of ASD."

(Ram, Sheena, Mariann A. Howland, Curt A. Sandman, Elysia Poggi Davis, and Laura M. Glynn. "Prenatal Risk for ASD: Fetal Cortisol Exposure Predicts Child Autism-Spectrum-Disorder Symptoms." Clinical Psychological Science (2018): 2167702618811079.)

39% more girls have Autism Spectrum Disorder than currently diagnosed

"The current study estimates that approximately 39 percent more girls should be diagnosed with ASD."

(Barnard-Brak, Lucy, David Richman, and M. Hasan Almekdash. "How many girls are we missing in ASD? An examination from a clinic-and community-based sample." Advances in Autism (2019).)

People with ASD have higher non-verbal than verbal skills; using abbreviated IQ-tests may misrepresent IQ

"The Fifth Edition of the Stanford-Binet Intelligence Scales (SB5; Roid, G. H. (2003). Stanford Binet intelligence scales (5th ed.). Itasca, IL: Riverside Publishing) is relatively new, with minimal published research on general populations and none with special populations. The present study provides information on the cognitive profiles of children with ASD (N=63) and on the whether the abbreviated battery is representative of the full scale. A high percentage of the children had significantly stronger nonverbal (vs. verbal) skills. This pattern was not related to Full Scale IQ, age or diagnostic subgroup. IQs derived from the abbreviated battery accounted for a large proportion of the variance in FSIQ relative to comparable abbreviated batteries. However, caution is warranted when using the abbreviated battery, as it misrepresents actual ability in a small percentage of cases."

(Coolican, Jamesie, Susan E. Bryson, and Lonnie Zwaigenbaum. "Brief report: Data on the Stanford–Binet intelligence scales in children with autism spectrum disorder." Journal of Autism and Developmental Disorders 38.1 (2008): 190-197.)