Thursday 8 May 2014

Oxidative Stress, Central Hypothyroidism, Autism and You

   Warsaw University of Life Sciences, Source: Wikipedia

Regular readers of this blog will have noticed there are some strange things going on related to endocrinology in the autistic brain; in effect there are low levels of certain critical hormones.

We saw in research from the Harvard Medical School that it seemed that oxidative stress in the brain affected the level of a key enzyme D2 (iodothyronine deiodinase type 2).  D2 has an important role; it converts the passive thyroid pro-hormone T4,  into the active thyroid hormone T3.  Without enough T3, you are said to be hypothyroid.  When the brain is affected, it is called central hypothyroidism.

As T3 is essential for cellular metabolism, growth and differentiation, and thus critical for brain development, thyroid deficiency during embryonic or early postnatal periods would likely lead to developmental abnormalities, including autism.

Now we have some follow up research from Harvard and Warsaw University.  The paper is more readable than many scientific papers, so click on the full version below.

“While the mechanism responsible for the decrease in brain T3 levels in ASD is unclear, the relationship between T3 and Hg (mercury) should not be that easily dismissed.

Our recent animal study of perinatal mercury exposure in rats supports the possibility that the environmental toxicants can affect brain deiodinases and thus affect brain TH (thyroid hormone) status even in absence of systemic hormonal deregulation

Total Hg levels were determined in human postmortem cerebellar and brain stem samples derived from both male and female ASD cases. The results of this analysis, presented in Fig. 4 as the male and female combined data, indicate no significant difference in Hg levels between control and ASD cases in either the brainstem or the cerebellar samples.

Thus, changes in oxidative stress levels reported here could also modulate D2 activity. It is of interest that TH regulates GSH levels in the developing brain and treatment of astrocyte cultures with TH results in increased GSH levels and improved antioxidant defense, suggesting that TH plays a positive role in maintaining GSH homeostasis and protecting the brain from oxidative stress. Thus lower T3 levels in ASD brain may exacerbate the oxidative stress.

The results presented here suggest that putamen is the brain region that exhibits not only an increase in oxidative stress and a decrease in T3 levels, but also most prominent changes in gene expression in ASD. Interestingly, the putamen's main function is to regulate movements and influence reinforcement and implicit learning, processes that rely on interaction with the environment; abnormal sensory reactions are part of autistic pathology. Thus, present study further implicates this brain region in autistic pathology.

Decreased brain TH levels and changes in gene expression in ASD brains, suggested by the present study, are likely to impact the developing brain and have clinical implications. It has been previously observed that deficiency of T3 during early postnatal periods impacts basic stages of development i.e. neurogenesis, cell migration of, and synaptogenesis that could contribute to downstream functional and structural damages observed in ASD brains. At this point, because the instability of D2 in the postmortem tissue and lack of detectable D3 activity we can only speculate on the molecular mechanisms involved in decreased TH in ASD brains. However, present data suggest that the role of TH in ASD pathology should not be dismissed prematurely and certainly requires further study, especially since correction of TH deficiency may offer new therapies.

Our results showed, for the first time, brain region-specific decrease in TH levels in the cortical regions of ASD male cases. Data reported here, although derived from a limited sample size, suggest the possibility of brain region-specific disruption of TH homeostasis in autistic brain. Furthermore, brain region-specific changes in TH-dependent gene expression reported here suggest disruption of gene expression that could possibly impact the developing brain and contribute to the autistic pathology. While the postmortem instability of brain deiodinases precluded further molecular studies, the role of TH in ASD pathology and TH-based new therapies warrant future studies.

The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism. “


We know that T3 is reduced in the autistic brain.  This may be because oxidative stress has reduced the level of the enzyme D2, but we cannot be sure, because the brain samples are old and D2 will decay with time.

The authors clearly hope that thyroid hormone-based therapies for autism will emerge.  Autistic people are likely to be euthyroid, so in their blood the thyroid levels are just fine; it is just in the brain the level of T3 is low. A successful therapy would raise the level of T3 in the brain, without affecting the level of T3 in the blood.

Reducing oxidative stress (if present) can only do good.  This is easily done with N-acetylcysteine (NAC).  If giving NAC reduces stimming/stereotypy, then the odds are that you have oxidative stress.  Oxidative stress appears to be chronic, it never goes away; you can treat it, but you cannot cure it.  We also saw this is the asthma research, where smokers were resistant to asthma drugs.  Even decades after ceasing to smoke, oxidative stress lingered and reduced the effectiveness of drugs.  In asthma the treatment for oxidative stress is NAC.

If you want a diagnostic test to establish central hypothyroidism (without any injections), this is easy.  Just give a small dose of T3 for a few days.  Before the thyroid has time to reduce its natural thyroid output, there will be a temporary increase in brain T3 levels.  If behavior improves notably for a day or two and then reverts, you have established a case of central hypothyroidism and seen how it affects behavior.

The scientific method of determining central hypothyroidism uses a test called the TRH stimulation test; but you do not get to see how behavior changes when T3 increases in the brain.

Also, note again that while mercury is definitely very bad for you, the study showed that the brains of people with autism had no more mercury than the control group.

We also see that while oxidative stress may cause a reduction in brain T3 levels, low T3 levels promote further oxidative stress.  So it is a self-perpetuating process.  This brings us back again to my venn diagram, where everything is inter-related. 


  1. Hi Peter,

    My daughter has been on Verapamil for just over a year now and on Bumetanide for the last 3 months. I have some questions about them that I will ask later. There is a more urgent issue I would appreciate your help on.

    My daughter has been having irregular menses, and her labs showed TSH 6.1 (v. high) and normal free t4. Her blood cortisol, dhea and prolactin were also high. The endocrinologist would like her to start levothyroxine 25mg, which is just t4. I talked to him about adding t3 or doing a natural desiccated thyroid like Armour, but he was reluctant. He is willing to add on either of those only after a few months of t4. HIs explanation was that t3 could have unpredictable effects with a very short half life, and porcine thyroid is very heavy on the t3 which accumulates over time (this is contradictory isn't it) and in the course of a year would skew the person to hyperthyroid with intermittent hypothyroid symptoms. Later in the day, I found a presentation by a doctor on treating hypothyroidism with compounded t4 and t3 combination in a sustained release formula. Can you weigh in on this please?

    The endocrinologist has also prescribed Metformin for the other hormonal symptoms, which he has diagnosed as pcos.


    1. Hi RG

      First of all I am not a doctor, I just read a lot of research.

      Did you tell the endocrinologist about the Verapamil? Did you try stopping the Verapamil and rechecking the hormone levels?

      Doctors almost everywhere believe that only T4 is ever necessary. T4 is a pro-hormone that should be converted to the active hormone T3 as needed by the body using the enzyme D2. If you are lacking in D2 you will not be able to convert T4 into T3.

      In most countries (i.e. outside North America) T3 is not even available.

      I did have a lengthy discussion with our pediatric endocrinologist and she saw no harm in giving a small dose of T3 and was happy to prescribe it even though T3 is not available where we live. In the end I obtained it from Mexico.

      In the US there are combinations of T3 and T4 available.

      I would first establish if your daughter is experiencing an unusual side effect of Verapamil. There are some people who cannot tolerate Verapamil.

    2. I did tell the endocrinologist about the Verapamil. He thought it could account for some of the rise in the prolactin. My daughter's TSH as far back as 2009 was closer to 4, which he tells me is still in the hypothyroid range. The American Thyroid Association likes it to be under 2.5, while he likes to get it close to 1.

      We are very dependent on Verapamil here, when we first started it last year, we had 45 days between seizures, which at that time, were occurring several times a month. Currently, the Verapamil (60mg x 3), Bumetanide 1mg and 900 mg of magnesium are required to keep things under control, behavior wise.

      Maybe I should try to amp up the D2 activity. I used to give her selenium which I stopped. Any more information on Kaempferol or other substances?

      When you did give your son the t3, were there any side effects?

      Many thanks,

    3. I found that T3 improved behavior, but he is euthyroid. I think in autism there is often low T3 in the brain, due to low D2. If I continue to add T3, I will encourage the thyroid to produce less T4, so for my son this was more of a diagnostic test than a therapy.

      It seems that oxidative stress affects D2. So this is another good reason to use NAC. We use 4 x 600 mg daily. If you do not already use antioxidants, I would suggest it is worth trialing.

  2. Hi Peter,

    Spoke to the endocrinologist, he would like to go five weeks on a very low dose t4, test, and then come in with additional t3. He insists that in his experience, in the long run, this is what works. He is not comfortable with t3 alone, he believes the t4 is needed to stablize. We have started the 25mg levothyroxine. Will keep you posted.

    Thank you,


    1. Hi RG, Good luck with the T4.

      I saw you tried progesterone, what effect did that have on the autism? Do you think this had an effect on puberty? Did you look at low dose pregnenolone/progesterone? It seem plausible that the (good) effects on GABAa receptors might be possible with tiny doses.

    2. I tried the progesterone primarily for seizures. My daughter's seizures were catamenial, and in November '13, they suddenly worsened. Instead of just one per month, we went to several. The autism also significantly worsened. Meltdowns, screaming, lots of SIB, none of which had been a problem earlier. We first tried oral progesterone, pretty useless. Then, the otc cream at about 25mg once a day. It did nothing for seizures, but improved the autism, especially would quell a meltdown. She would often also smile and say 'good, good', and get happy immediately after applying.

      At this point, since the seizures were no better, we started the Modified Atkins Diet (MAD). That first month was magic, no seizures, the autism improved to a point that was better than Nov '13. She had one catamenial seizure at 30 days, but we could deal with that, since it was predictable. Unfortunately, we had to move for a year to a place that was a couple of hours away, and it was horrendous. The air was horrible there, and she began falling into seizures every week. The autism worsened again and we had a new entry: anxiety. We went to a compounded progesterone cream and started at about 90mg per day and moved up to 135mg. Beyond that, there was a negative reaction. Never tried micro doses. After being on it for over a year, we stopped it last month as I did not feel it was doing anything significant. It was very good at stopping SIB and defusing a meltdown, but so are verapamil, magnesium and bumetanide. It did not appear to have any particular effect on menses. It might be worth revisiting with micro doses a little later, after we settle down with the thyroid medications.

      We moved back earlier this year, but she seems to be suffering from a different kind of allergy here. My guess is that the autism and the seizures worsened due to severe pollen allergies caused by the drought that we have been having the last three years. In fact, I remember clearly that in '13 we never had any kind of winter, and we had cherry blossoms in October. Most of my annuals stayed in bloom through Christmas. Strangely, zyrtec is not consistently effective here, whereas in the other house it was. There the allergies were from agricultural pesticides and fertilizers borne on strong winds.

    3. Thank you for the detailed explanation.

  3. Hi Peter,
    We have been using clonzepam for the past 3 weeks around .25 -0.5 mg 2X a day, with no noticeable improvements.
    I am about to trial Pantogam Active as I suspect our docs will likely not prescribe baclofen. I am confused about dosing. The recommendations for Pantogam is around 500-3000 mg 2X a day, as confirmed in the studies you embedded in your posts.
    The label's recommendations for Pantogam Active are 300-2400 mg 2X a day.
    These are far higher dosages than for baclofen or arbaclofen, yet I thought this was a comparable drug.
    Your thoughts?
    Thanks very much,

    1. Nancy, the clonazepam dose that does help some people is 0.025 to 0.05 mg once a day. Did you try 10x this dose? Pantogam is similar to Baclofen, but that does not mean the dosage has to be similar. I would follow the instructions on the label.

  4. I misspoke. We have .025 tablets and I had upped it to 2 of those. But I have been doing twice a day. That part is correct. I will go back to once daily and see if that is more effective.
    Thanks, Peter.


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