Beauty is in the eye of the beholder
In the mass
media it is now popular to dismiss the fact that autism is far more prevalent
on boys than girls. In the scientific literature, fortunately, they stick to
the facts and much is written about the sex differences in autism.
As we have
seen in earlier posts, females have some natural defences against autism. They
have two X chromosomes and of course they have those all-important
neuroprotective female hormones (estrogen/estradiol, progesterone etc.). In
effect, the more female you are, the more protection you have against
idiopathic autism and any X-chromosome linked single gene autism. So a girl
with Fragile-X syndrome is likely to be far less affected than her brother with
same condition.Recall that we all have 23 pairs of chromosomes and that the 23rd set contains two Xs in girls and in boys one X and one Y. The girls’ “spare” X chromosome is also what gives them their feminine features.
It is
interesting to look what happens to females who lack part of their second set
of X- chromosomes. This diagnosis is called Turner Syndrome. As you might have
guessed people with Turner Syndrome have much lower levels of female hormones
and a higher incidence of autism, although some people find this controversial.
The autism-like characteristics of TS include:-
· Impairments in social
functioning
· Impairments in face and
emotion processing
· Spatial executive
deficits
· Poor social coping skills
and increased immaturity
· Hyperactivity and
impulsivity
Turner syndrome occurs
in 50 per 100,000 live-born
females. Autism occurs about ten times for frequently, so about 500 per 100,000
live-born females. Turner syndrome provides
the extreme case of what happens when females have too little
estrogen/estradiol.
I think you will find a
large group of females with idiopathic autism (no identified genetic defects)
have/had low levels of estradiol. I think this is the reason that facial
recognition studies show that some females with idiopathic autism look
different, (as do many boys, of course). We already know that most single gene
types of autism produce tell-tale signs, often on the face (big ears, wide
face, big/small head etc).
I am not suggesting that
there is anything wrong with looking different; rather it may be a useful
diagnostic tool and not an expensive or invasive one. Physical variation has
long been used to identify genetic syndromes, before genetic testing became
widely available.
Physical variation inside your
head
We saw in an earlier
post that MRI scans of the autistic brains actually do often show subtle
differences, particularly when you use software to read them, rather than the
naked eye. Traditionally doctors say that MRIs are “normal” in autism and
cannot be used to diagnose it. Yet in a recent studies machine reading of MRIs
was able to identify 70%-96% of autism cases.
Some of these are scans taken before birth.
This is interesting,
because ultimately you might bypass the current very slow and subjective observational
diagnosis process.
MRIs show a brain anomaly in nearly 70 percent of babies
at high risk of developing the condition who go on to be diagnosed, laying the
groundwork for a predictive aid for pediatricians and the search for a
potential treatment
Predicting the future with brain imaging
In a new study, Emerson et al. show that brain
function in infancy can be used to accurately predict which high-risk infants
will later receive an autism diagnosis. Using machine learning techniques that identify
patterns in the brain’s functional connections, Emerson and colleagues were able to predict with greater
than 96% accuracy whether a 6-month-old infant would develop autism at 24 months
of age. These findings must be replicated, but they represent an
important step toward the early identification of individuals with autism
before its characteristic symptoms develop.
MRI
scanners are very widely used, but you do have to keep very still inside when
they are in operation. The even harder part is the reading of the data. It is
clear that some standardized machine reading (A/I artificial intelligence)
process is required to notice every possible variation. You could have a centralized location where you just
submit your MRI data, the center gets to keep the data and learn from it; and
you get their insight as to what differences there might be.
Facial Differences vs MRI Brain
Differences
I like to keep things
simple and under my control. In the
short term we have to settle for facial differences, since any well-managed MRI
process will be decades away.
Hormonal Variation in Autism
Hormonal differences
were one of the key areas I identified years ago in this blog. Big/small heads
result from disturbances in pro-growth signalling pathways. We should expect
variations in bone-age, early/late onset of puberty and indeed big variations
in height and weight.
In Turner Syndrome, the
girls tend to be very short and they are often treated with growth hormones, as
well as female/feminizing hormones.
Great caution has to be
taken when treating children with any hormones. When children are treated, it
is for serious reasons like not achieving puberty, or having a serious growth
delay (being very short).
Hormone Therapy During Pregnancy
In some countries
hormones are given during pregnancy although I think this would be seen as
odd/risky in some advanced countries.
We have already seen
that couples who have difficulty producing a child often have a family history
that includes autism. It was proposed by one serious fertility expert that what
helps prevent miscarriage also helps prevent autism. This did sound odd when I
first read about, but when you look in more depth there is a basis for this
idea.
That expert has these two
websites:-
Progesterone supplements have been recommended for more
than 50 years for women struggling with infertility, but research now shows
they can also help prevent miscarriage.
Estradiol is
sometimes prescribed during pregnancy.
Testosterone is
produced naturally during pregnancy.
All this is clearly
beyond the scope of this blog, but perhaps altered female/male hormones during
pregnancy might be a biomarker of some future autism and female hormones might
be a protective therapy in the subgroup of pregnant mothers with low levels of
these hormones and/or high levels of testosterone. Recall that human trials in the hospital ER have shown certain substances are highly neuroprotective (progesterone, atorvastatin etc) and when administered immediately after a traumatic brain injury markedly improve the outcome.
Hormone Therapy for Autism
Hormone therapy
in people with autism would be controversial, but we saw in an earlier post
that via RORα the balance between testosterone and estradiol affects numerous
biological relevant to autism.
Many
pictures of girls/women with autism, that you can view online, suggest reduced
levels of estradiol. Faces look more boy-like. Many males with autism are
reported to have physical features of high testosterone and low estradiol.
One example of many:-
https://www.npr.org/2017/11/28/566788182/navigating-life-on-campus-when-youre-on-the-autism-spectrum
Both faces in the above article show clear
indications of autism. Since both young people do have autism, this should not
surprise anyone.
My own
conclusion is that if you have autism or Asperger’s, a little extra estradiol
could therapeutic, particularly if you have physical features that reinforce
this.
There are of
course many males and females with autism who are physically indistinguishable
from the rest of the world. The point of this post is to highlight that visible
differences may help to define the sub-type of autism and indicate possibly
effective therapies, that exist today.
Obesity and Estradiol
In an
earlier post on estradiol, I pointed out that in males estradiol is made in
your adipose (fat) tissue. In the US many people with autism are overweight, in
part due to side effects from their likely un-needed psychiatric medications; this
has the hidden benefit of increasing their estradiol levels, feminizing their
behavior slightly and shifting RORalpha in the right direction.
This also
means that losing weight should be helpful to obese females with estrogen
receptor positive breast cancer. Research does support this.
A very thorough paper on Turner Syndrome:-
Asperger’s and too much Estradiol?
We saw in
earlier posts that much autism is associated with reduced expression of
estrogen receptor beta and low aromatase, so high testosterone and low
estradiol.
We have seen
on many occasions that when one extreme exists in autism, so usually does the
other; so many big heads, but also some tiny ones, NMDAR hypofunction, but also
hyperfunction.
There was a
lot of talk a while back in the media about children undergoing therapy to
change their gender, and it was highlighted that Asperger’s was much over-represented
in this group. One expert got into trouble for suggesting that their autism was
causing them to obsess about their identity and so mistakenly convince a boy
that he would rather be a girl. It seems
that these days some clinicians are then all too willing to provide drug
therapy and then operate on them, to make them female. I do wonder if perhaps some of these boys
with Asperger’s might have the other extreme of aromatise. That would give them
too little testosterone and too much Estradiol.
I think
measuring these hormones is quite a good idea, as I keep repeating, they go on to
affect the critical “switch” RORα, which
then impacts a large number of biological processes implicated in autism. In other words you can try to normalize a
wide range of important autism variables, just be tweaking RORα, via estradiol/testosterone.
A boy with
high testosterone, and so low estradiol, will likely exhibit physical signs of
this, just like the girl with low estradiol. These are just pieces of the
puzzle, in plain view, that can be used to understand each specific case of
autism. And no machine reading of an MRI is required.
For those left wanting more:
Turner syndrome (TS) is a neurogenetic disorder characterized by
partial or complete monosomy-X. TS is associated with certain physical and medical features including
estrogen deficiency, short stature and increased risk for several
diseases with cardiac conditions being among the most serious. Girls with TS
are typically treated with growth hormone and estrogen replacement therapies to
address short stature and estrogen deficiency. The cognitive-behavioral
phenotype associated with TS includes strengths in verbal domains with
impairments in visual-spatial, executive function and emotion processing.
Genetic analyses have identified the short stature homeobox (SHOX) gene as being
a candidate gene for short stature and other skeletal abnormalities associated
with TS but currently the gene or genes associated with cognitive impairments
remain unknown. However, significant progress has been made in describing
neurodevelopmental and neurobiologic factors underlying these impairments and
potential interventions are on the horizon
We utilized an ultrasensitive assay to study estradiol levels in
34 girls with TS and 34 normal age-matched prepubertal girls between the ages
of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/-
4.9 pmol/l estradiol equivalents) was significantly lower than in the normal
prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01).
Girls with TS were significantly shorter, and weighed less than the normal
prepubertal girls, as expected. The estradiol level was not significantly
correlated with height, bone age,