On 2015 Oct 10, Peter Good commented:

Baron-Cohen and colleagues here present “the first direct evidence of elevated fetal steroidogenic activity in autism” – primarily elevated androgenic hormones of the Δ4 pathway androstenedione and testosterone. They propose that high fetal testosterone explains the “extreme male brain” of autism [Baron-Cohen S, 2005] – why these children appear to be extreme versions of normal male intelligence, as Asperger noted many years ago [Frith 1991].

But high fetal testosterone does NOT readily explain why autistic children are often anxious, even timid, in the presence of others. Markram and colleagues pointed out that Kanner (1943) observed abnormal anxiety and phobias in these children, as other researchers have since [Markram K, 2010]. Melvin Konner noted that early pioneers of autism research Niko and Elisabeth Tinbergen detected signs of fear in these children in social situations, and “reasoned that exceptionally timid children might be at risk for developing the disorder if they grew up in a sufficiently threatening – or perhaps for them, merely a very intrusive – social environment.”[Konner 1982] Since testesterone allays fear [Konner], why are autistic children timid?

One explanation may be androstenedione, which the present study also found at higher than normal levels in amniotic fluid of these children. Androstenedione is a weak androgen precursor of testosterone, estrone, and estradiol, the primary estrogen. However, Taylor and colleagues concluded that its effects on rat sexual behavior reveal that androstenedione leaves “behavioral footprints” different from testosterone [Taylor GT, 2012]. Jacklin and colleagues assessed timidity in infants by their reaction to fear-provoking toys. Low timidity in boys was associated with higher levels of testosterone at birth – but not androstenedione [Jacklin CN, 1983]. Ward pointed out prenatal stress “causes an increase in the weak adrenal androgen, androstenedione, from the maternal or fetal adrenal cortices, or from both, and a concurrent decrease in the potent gonadal androgen, testosterone.”[Ward IL, 1972] This happens because release of androstenedione and testosterone from the testes is triggered by luteinizing hormone (LH) from the pituitary; high adrenal androstenedione suppresses LH release by negative feedback.” Do high levels of androstenedione differentiate the brain of a male fetus BEFORE they turn to testosterone and estrogen?

A second challenge to high prenatal testosterone is the certainty the brain overgrowth of autism happens after birth, not before. Courchesne and colleagues found that children with autism have smaller heads at birth, then a sudden excessive increase in head size beginning a few months after birth and lasting six to 14 months: “[O]ur study found evidence of neonatal brain undergrowth followed by rapid and excessive postnatal brain growth beginning in the first few months that precedes the clinical behavioral onset of autism.”[Courchesne E, 2003] This sounds like postnatal catch-up growth in infants born prematurely or whose fetal head growth was restrained for any reason [Cockerill J, 2006]. Or was it due to the usual postnatal testosterone surge in male infants within a few months of birth [Swaab DF, 2007]? Courchesne et al. didn’t mention the surge; some of the infants they studied were girls.

Herbert reviewed the pathology of these large brains in ASD: disproportionate proliferation of white matter, yet diminished connectivity, and neuroinflammation and astrogliosis [Herbert MR, 2005]. She and her colleagues previously found the increased brain volume was confined to the subcortical white matter, especially in the frontal lobes, and did not include the deep white matter, e.g. corpus callosum: “This lack of expected association between radiate compartment and corpus callosum volume suggests that the white matter volume increase predominantly involves short and medium-range corticocortical connections within hemispheres, with less, if any, involvement of connections between hemispheres.” [Herbert MR, 2004] Intrahemispheric white-matter tracts are testosterone-dependent; interhemispheric white-matter tracts estrogen-dependent [Baron-Cohen S, 2005]. If postnatal brain overgrowth in ASD is catch-up growth, overgrowth of testosterone-dependent structures implies prenatal undergrowth of the structures. Yet insufficient estradiol might also explain smaller brains at birth. But then why doesn’t postnatal brain overgrowth favor estrogen-dependent structures?

These arguments have also been posted online in my paper Chronic neurochemical cerebral asymmetry and dysconnection in autism. Implications of a personal trial of oral citrulline + taurine at: http://www.autismstudies.net

references

Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science 2005;310: 819–823.

Cockerill J, Uthaya S, Doré CJ, Modi N. Accelerated postnatal head growth follows preterm birth. Arch Dis Child Fetal Neonatal Ed 2006;91:F184–F187.

Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA 2003;290(3):337–344.

Frith U. Autism and Asperger Syndrome. Cambridge, England: Cambridge University Press; 1991.

Herbert MR, Ziegler DA, Makris N, Filipek PA. Kemper TL. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 2004;55:530–540.

Herbert MR. Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 2005;11:417–440.

Jacklin CN, Maccoby EE, Doering CH. Neonatal sex-steroid hormones and timidity in 6-to-18-month-old boys and girls. Dev Psychobiol 1983;16:163–168.

Konner M. The Tangled Wing. Biological Constraints on the Human Spirit. New York: Holt, Rinehart and Winston; 1982.

Markram K, Markram H. The intense world theory – a unifying theory of the neurobiology of autism. Front Hum Neurosci 2010;4:224.

Swaab DF. Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab 2007;21:431–444.

Taylor GT, Dearborn JT, Maloney SE. Adrenal steroids uniquely influence sexual motivation behavior in male rats. Behav Sci 2012;2:195–206.

Ward IL. Prenatal stress feminizes and demasculinizes the behavior of males. Science 1972;175:82–84.

On 2015 Oct 10, Peter Good commented:

Baron-Cohen and colleagues here present “the first direct evidence of elevated fetal steroidogenic activity in autism” – primarily elevated androgenic hormones of the Δ4 pathway androstenedione and testosterone. They propose that high fetal testosterone explains the “extreme male brain” of autism [Baron-Cohen S, 2005] – why these children appear to be extreme versions of normal male intelligence, as Asperger noted many years ago [Frith 1991].

But high fetal testosterone does NOT readily explain why autistic children are often anxious, even timid, in the presence of others. Markram and colleagues pointed out that Kanner (1943) observed abnormal anxiety and phobias in these children, as other researchers have since [Markram K, 2010]. Melvin Konner noted that early pioneers of autism research Niko and Elisabeth Tinbergen detected signs of fear in these children in social situations, and “reasoned that exceptionally timid children might be at risk for developing the disorder if they grew up in a sufficiently threatening – or perhaps for them, merely a very intrusive – social environment.”[Konner 1982] Since testesterone allays fear [Konner], why are autistic children timid?

One explanation may be androstenedione, which the present study also found at higher than normal levels in amniotic fluid of these children. Androstenedione is a weak androgen precursor of testosterone, estrone, and estradiol, the primary estrogen. However, Taylor and colleagues concluded that its effects on rat sexual behavior reveal that androstenedione leaves “behavioral footprints” different from testosterone [Taylor GT, 2012]. Jacklin and colleagues assessed timidity in infants by their reaction to fear-provoking toys. Low timidity in boys was associated with higher levels of testosterone at birth – but not androstenedione [Jacklin CN, 1983]. Ward pointed out prenatal stress “causes an increase in the weak adrenal androgen, androstenedione, from the maternal or fetal adrenal cortices, or from both, and a concurrent decrease in the potent gonadal androgen, testosterone.”[Ward IL, 1972] This happens because release of androstenedione and testosterone from the testes is triggered by luteinizing hormone (LH) from the pituitary; high adrenal androstenedione suppresses LH release by negative feedback.” Do high levels of androstenedione differentiate the brain of a male fetus BEFORE they turn to testosterone and estrogen?

A second challenge to high prenatal testosterone is the certainty the brain overgrowth of autism happens after birth, not before. Courchesne and colleagues found that children with autism have smaller heads at birth, then a sudden excessive increase in head size beginning a few months after birth and lasting six to 14 months: “[O]ur study found evidence of neonatal brain undergrowth followed by rapid and excessive postnatal brain growth beginning in the first few months that precedes the clinical behavioral onset of autism.”[Courchesne E, 2003] This sounds like postnatal catch-up growth in infants born prematurely or whose fetal head growth was restrained for any reason [Cockerill J, 2006]. Or was it due to the usual postnatal testosterone surge in male infants within a few months of birth [Swaab DF, 2007]? Courchesne et al. didn’t mention the surge; some of the infants they studied were girls.

Herbert reviewed the pathology of these large brains in ASD: disproportionate proliferation of white matter, yet diminished connectivity, and neuroinflammation and astrogliosis [Herbert MR, 2005]. She and her colleagues previously found the increased brain volume was confined to the subcortical white matter, especially in the frontal lobes, and did not include the deep white matter, e.g. corpus callosum: “This lack of expected association between radiate compartment and corpus callosum volume suggests that the white matter volume increase predominantly involves short and medium-range corticocortical connections within hemispheres, with less, if any, involvement of connections between hemispheres.” [Herbert MR, 2004] Intrahemispheric white-matter tracts are testosterone-dependent; interhemispheric white-matter tracts estrogen-dependent [Baron-Cohen S, 2005]. If postnatal brain overgrowth in ASD is catch-up growth, overgrowth of testosterone-dependent structures implies prenatal undergrowth of the structures. Yet insufficient estradiol might also explain smaller brains at birth. But then why doesn’t postnatal brain overgrowth favor estrogen-dependent structures?

These arguments have also been posted online in my paper Chronic neurochemical cerebral asymmetry and dysconnection in autism. Implications of a personal trial of oral citrulline + taurine at: http://www.autismstudies.net

references

Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science 2005;310: 819–823.

Cockerill J, Uthaya S, Doré CJ, Modi N. Accelerated postnatal head growth follows preterm birth. Arch Dis Child Fetal Neonatal Ed 2006;91:F184–F187.

Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA 2003;290(3):337–344.

Frith U. Autism and Asperger Syndrome. Cambridge, England: Cambridge University Press; 1991.

Herbert MR, Ziegler DA, Makris N, Filipek PA. Kemper TL. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 2004;55:530–540.

Herbert MR. Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 2005;11:417–440.

Jacklin CN, Maccoby EE, Doering CH. Neonatal sex-steroid hormones and timidity in 6-to-18-month-old boys and girls. Dev Psychobiol 1983;16:163–168.

Konner M. The Tangled Wing. Biological Constraints on the Human Spirit. New York: Holt, Rinehart and Winston; 1982.

Markram K, Markram H. The intense world theory – a unifying theory of the neurobiology of autism. Front Hum Neurosci 2010;4:224.

Swaab DF. Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab 2007;21:431–444.

Taylor GT, Dearborn JT, Maloney SE. Adrenal steroids uniquely influence sexual motivation behavior in male rats. Behav Sci 2012;2:195–206.

Ward IL. Prenatal stress feminizes and demasculinizes the behavior of males. Science 1972;175:82–84.