I am
returning to an old theme of mine, which is my hypothesis that the thyroid
releasing hormone (TRH) may be of therapeutic value in autism. I have been reading up on what some endocrinologists
are doing the US and also looking a bit deeper into the underlying biology of
the related hormones and thinking about my research sample of one, Monty aged
10 with ASD. My original hypothesis was argued in an earlier post.
Since none
of the TRH researchers care to reply to my emails, I decided to refine and
document my hypothesis further and then plan to go and see a child endocrinologist for
myself. In most countries, the doctor does
the talking and the patient does the listening, so I know that I need something
unusual; I called it “an open minded endocrinologist”.
Peter’s TRH & Central
Hypothyroidism Theory
Research has
documented which parts of the autistic brain are often damaged. The Purkinje cell layer and the cerebellum in
general has been a focus of my blog; but the hypothalamus, which is very close by, is
also known to be different in autistic people.
It has been shown that diminished grey matter exists in a region of the hypothalamus, which
synthesizes the behaviorally relevant hormones oxytocin and arginine
vasopressin. My pet hormone “TRH” is
also produced in the hypothalamus. The
pituitary gland is a protrusion off the bottom of the hypothalamus at the base of the brain.
The pituitary gland is functionally connected to the hypothalamus via a small
tube called the pituitary stalk. The pituitary gland secretes nine hormones
that regulate homeostatis; one of these is TSH (thyroid stimulating
hormone).
In summary, TRH from the damaged hypothalamus travels down to the pituitary
gland where it triggers the release of TSH.
TSH travels a bit further to the thyroid gland where two important
hormones, T3 and T4, are produced.
When the levels of T3 and T4 are low a condition called hypothyroidism
exists. T4 is a so-called pro hormone of
T3.
I have already noted that when Monty was a young toddler he was tall for his age,
about the 90th percentile; aged 10 his is now about the 25%
percentile. When I started this blog, I
saw in the old autism literature there are lots of studies about head
circumference in autism. In summary they
found that in autism the head (and by inference the brain) grows very fast in
the first couple of years and then by 3 or 4 years of age the brain has prematurely reached adult size. The brain grew faster than normal and certain
parts developed abnormally. I did not
see any research into abnormal development in height. It would be very easy to study this, since in
most countries a child’s height is regularly recorded.
When I recently checked to see what are the effects of hypothyroidism in typical
children, I found interesting reading:-
Effects of
Hypothyroidism During Infancy. Transient hypothyroidism is
common among premature infants. Although temporary, severe cases can cause
difficulties in neurologic and mental development.
Infants born with permanent congenital (inborn) hypothyroidism
need to receive treatment as soon as possible after birth to prevent mental
retardation, stunted growth, and other aspects of abnormal development (a
syndrome referred to as cretinism). Untreated infants can lose up to three to
five IQ points per month during the first year. An early start of lifelong
treatment avoids or minimizes this damage. Even with early treatment, however,
mild problems in memory, attention, and mental processing may persist into
adolescence and adulthood.
Effects of Childhood-Onset Hypothyroidism. If
hypothyroidism develops in children older than 2 years, mental retardation is
not a danger, but physical growth may be slowed and new teeth
delayed. If treatment is delayed, adult growth could be affected. Even with
treatment, some children with severe hypothyroidism may have attention problems
and hyperactivity.
Hypothyroidism is usually caused by a failure of the thyroid gland. TRH is being released to the pituitary, which
the produces TSH. The problem is in the
thyroid. The cure is usually to give T4
in tablet form. The body is usually able
to produce T3 from the T4.
Role of D2
and D3 & Oxidative Stress
Both T3 and T4,
are produced in the thyroid gland. The ratio of T3 to T4 released into the
blood is 1:20. Both T3 and T4 then reach
the individual body organs, where the prohormone T4 is converted to the
biologically active hormone T3. The organ/tissue levels of T3 are regulated
locally primarily by the activity of two different selenoenzymes, deiodinases
type 2 (D2) and type 3 (D3), although deiodinase type 1 is also involved. In
the CNS, approximately 70-80% of T3 originates from intracerebral T4 to T3
conversion, while the plasma contribution amounts to 20-30 % and D2 is responsible for most of the T3
supply within the brain.
The major
source of the biologically active hormone T3 in the brain is the local
intra-brain conversion of T4 to T3, while a small fraction comes from
circulating T3.
As evidence
derived from in vitro studies suggests, in response to oxidative stress D3
increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010). As we know in the autistic brain we have a
lot of oxidative stress.
Furthermore, in
ASD, the lower intra-brain T3 levels occur in the
Absence of a
systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity
of D3.
Central Hypothyroidism
There is a supposedly rare condition called Central Hypothyroidism, which occurs when the
pituitary gland does not produce enough TSH in response to TRH. In the research jargon they call it “a
blunted response”. Note that blood levels of TSH, T3 and T4 can be normal in cases of central hypothyroidism.
Research has
long ago shown that in autistic children often have a blunted response of TSH to
TRH. Interestingly in many psychiatric
conditions, like depression, research also shows a blunted response.
In the US,
psychiatrist have longed prescribed the hormone T3 for depression. I cannot find much in the way of explanation
by psychiatrists of this, other than that some endochronologists do not seem to
approve.
In theory if
you are low on T3 and T4, the therapy is to give just T4. But as we
learned above, if D2 and D3 are misbehaving T3 will not be produced as
required.
In the
“rare” cases of central hypothyroidism the researchers report being able to
correct T4 quite easily but not T3. So
their bodies are not converting enough T4 into T3, because D2 and D3 levels are
out of balance.
So the Peter theory has to evolve
In autism
there is very likely to be central hypothyroidism, a deficiency of D2 in the
brain causes low T3 and I conjecture that there is also a reduced level of TRH
being produced in the hypothalamus. Both the hypothalamus and the pituitary gland
are under-responsive. As a result
many hormones are going to be reduced including TRH, TSH, oxytocin, arginine
vasopressin and others.
Because TRH also has
secondary, only recently understood, behavioral effects, the central hypothyrodism
symptoms fits nicely with my earlier TRH theory.
In the US
some “holistic” doctors specialized in autism have long been claiming that the
majority of kids with ASD are hypothyroid.
They claim that the modern T3 and T4 blood tests are “inaccurate” and
that the old TRH stimulation test is more “accurate”. They then end up prescribing supplementary T3
and T4. This always looked odd to me; in
fact it is yet another case of getting the right answer, but for the wrong
reason.
The perfect
solution might have been just to give TRH.
You cannot do this because the half-life of TRH is just a few minutes
and it needs to be delivered into a vein.
A nasal TRH spray is being developed
with funding from the US military. TRH
has mood changing properties and the military has a big problem with suicide.
My idea of
using a TRH analog, such as Taltirelin Hydrate, is practical since it has a
long half-life and can be taken orally.
It is licensed as a drug, but only in Japan.
It also has a reduced effect on TSH, so you get the benefit of the behavioural
properties of TRH rather than just producing more TSH. This avoids the patient then going hyperthyroid.
A word from the Harvard Medical School
After
interest in the 1970s researching autism and the thyroid, not much has been
written for decades. Recently a paper
was published by researchers at the Harvard Medical School showing how
oxidative stress in the brain, if present, would disrupt thyroid hormone
homeostatis. It has been a long time
coming, but it looks like their thinking is spot on.
According to
this hypothesis, brain region-specific oxidative stress in autism may be associated
with increased D3 and decreased D2 activity resulting in a region-specific T3 deficiency
in the brain. Future human studies utilizing the CSF of living ASD individuals
or postmortem
brain tissue of ASD donors will support its validity. Such findings would have several
significant implications. They may result in methods of early ASD diagnosis; detection
of high brain D3 levels in postmortem human brains may suggest the benefits of measuring
the levels of its product (rT3) in the CSF of living patients to assess the
risks, monitor the disease progression and efficacy of ongoing treatment.
Furthermore, several tissue-specific
and TH receptor (TR)-specific thyromimetics have been developed as potential
treatment for atherosclerosis, obesity and Type 2 diabetes and might be able to
correct local brain TH deficiency without systemic thyrotoxicity (Baxter and
Webb, 2009) and may thus be considered as potential therapeutic agents.
Finally, confirmation that autism may be associated with increased D3 and
decreased D2 activity resulting in a region specific T3 deficiency in the brain
could lead to or reinforce dietary treatments, because D2 activity can be
modulated not only by selenium but also by xenobiotic compounds (da-Silva
et al., 2007). In
conclusion, TH
abnormalities in autism warrant a second look.
This paper
from Harvard is encouraging and not only concludes that thyroid abnormalities
in autism warrant a second look, but suggests ways to raise the level of D2 and
correct local brain hypothyroidism
The flavonoid
kaempferol looks interesting and there is also much written about its
anti-diabetic effects. This would be a
way to raise the amount of D2 and consequently T3 in the brain. This might be more effective that just
supplementing T3.
By the way,
just look at all the other things claimed of this flavonoid:-
Numerous preclinical studies have shown kaempferol and some
glycosides of kaempferol have a wide range of pharmacological activities,
including antioxidant, anti-inflammatory, antimicrobial, anticancer,
cardioprotective, neuroprotective, antidiabetic, antiosteoporotic,
estrogenic/antiestrogenic, anxiolytic, analgesic, and antiallergic activities.
Kaempferol consumption is also correlated with a reduced lung
cancer incidence.
Kaempferol may be a potent prophylactic against NOX-mediated
neurodegeneration
If you like natural cures, you will like this paper. Take a look at page 28.
As with
other flavonoids, there is low bioavailability – they are absorbed by the body in
tiny quantities. And they are VERY expensive.
Conclusion
I wish the
Harvard Medical School would follow up fast on its own research, so I do not have
to rely on the internet writings of “holistic” doctors. As the Harvard paper concluded “TH abnormalities in autism warrant a second look”.
Oral T3 clearly
does enter the brain in marked quantities, otherwise I suppose US psychiatrists
would not keep using it with their depressed patients. Research shows that most T3 in the brain
originates from T4 converted there by D2.
This implies to me that an alternative therapy would be to give something like kaempferol to raise the level of
D2. The problem, as with other useful flavonoids,
like Quercetin and Rutin, is low bioavailability – they are absorbed by the
body in tiny quantities. Kaempferol
appears to have the basis of being a wonder drug, but let's wait 20 years to
see.
In the meantime,
I will review all this with my sought for “open minded endochronologist”. All I can measure is TSH, T3 and T4 in the
blood, I cannot even guess at T3 or D2 in the brain. The old TRH stimulation test involves lots of
needles and that is something I have to try and avoid. Autistic kids don’t sit still for
needles.
