3-Iodothyronamine ( T1AM ) administered to rodents induce a hypometabolic state

[Iritu1021]

Learner1, I realized I skipped over your question to antibodies yesterday. H2 receptors are involved in antibody production. I've been through the whole "autoimmune theory" of POTS before and I didn't find it helpful. My impression was that in my sick states my body makes increased numbers of antibodies to literally everything - food, all viral antigens, thyroid tissue, etc. Whatever you test for, you are bound to find something. When there is poor tissue perfusion, there is going to be some tissue destruction, and any issue destruction generates antibody, and if you get too much histamine stimulation, the body just cranks up the volume of the production. According to Wikipedia, H2 (histamine) receptors inhibit antibody synthesis, T-cell proliferation and cytokine production antibody synthesis, and H4 receptors regulate mast cell chemotaxis.

The interesting question is why IVIG works in so many cases of both CFS and POTS. Could it be through helping to overcome the immune deficiency and defeat the pathogen within thyroid? It's one option. I always had low to moderate thyroid antibodies but large areas of inflammation on my thyroid ultrasound - so I'm more inclined to believe that the antibody generation was a secondary process next to viral infection that was going on in there. (There is now a strong link between EBV and autoimmune thyroiditis). Over the years the low level antibodies would probably add us to some real damage to cause true hypothyroidism.

That's just my interpretation at this point, hope it makes sense...

 

[Iritu1021]

Pattismith, sorry I confused you with another person on that threat who said she was taking levothyroxine. That's right, I remember now, you have euthyroid sick, and I agree that it's different. The question is why your body is keeping T3 low - if it's a mistake or a compensatory mechanism for lack of T1AM. Because maybe it's

Also, from what I read in those rodent studies, it didn't seem like T3 and T1AM acutally antagonize each other on the receptor level, more like they just exert a different set of metabolic effects on the DNA level. They probably have a built-in feedback or shared regulatory mechanism to keep each other in check. So perhaps until one is able to go up, the other one won't go up either - if that happens it causes dysautonomia which in my experience is much worse. The body probably is better adopt to being in "hibernation mode" than in dysautonomic mode where the ratio in these hormones becomes unbalanced.

Have you checked your orthostatic blood pressure to see if you have POTS? How does your standing pulse change before and after you take T3? For me, whenever T3 would start wearing off, I'd get low flow POTS. High doses of NDT and iodine on other hand give me high flow POTS. Seems like it's constantly shifting vasodilation - vasoconstriction in my vasculature which I think is due to the histamine-norepinephrine imbalance.

 

[pattismith]

@Iritu1021 ,

no I don't have POTS nor Mastocyte Activation.

Concerning T1AM blocking TH, did you read this study?

Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine
2010
Abstract
Thyroid hormone transporters are responsible for the cellular uptake of thyroid hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid hormone receptors.

A recently discovered thyroid hormone derivative, 3-iodothyronamine (T1AM), has distinct biological effects that are opposite those of thyroid hormone.
Here we investigate the effects of T1AM on thyroid hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid hormone transporters MCT8 and MCT10, and show that T1AM displays differential inhibition of T3 and T4 cellular uptake by these transporters.

T1AM inhibits T3 and T4 transport by OATP1A2 with IC50 values of 0.27 and 2.1 µM, respectively.
T4 transport by OATP1C1, which is thought to play a key role in thyroid hormone transport across the blood-brain barrier, is inhibited by T1AM with an IC50 of 4.8 µM.
T1AM also inhibits both T3 and T4 uptake via MCT8, the most specific thyroid hormone transporter identified to date, with IC50 values of 95 and 31 µM, respectively. By contrast, T1AM has no effect on thyroid hormone transport by OATP1B3 and MCT10.
Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T1AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.

 

[Iritu1021]

Ok, then maybe it does have immediate antagonistic effect in addition to long term genomic effects. I do remember seeing that study but I must have glanced over the meaning because of all those complicated names, thanks for pointing it out! That would actually explain a lot about the immediate onset of action we both feel (nobody wanted to believe me that I can feel a huge difference from thyroid within less than an hour of taking it).

As for POTS, what I meant is I noticed that my changes in horzontal and upright blood pressure and heart rate were consistently different depending on the level of T3. My standing heart rate always went down right after taking T3 and then it would go up when I was due for the next dose. It might not have been something I would really know unless I was regularly checking for it. T1AM is supposed to cause bradycardia and excess T3 is supposed to cause tachycardia so I still can't wrap my mind around it.

 

[pattismith]

Ok, then maybe it does have immediate antagonistic effect in addition to long term genomic effects. I do remember seeing that study but I must have glanced over the meaning because of all those complicated names, thanks for pointing it out! That would actually explain a lot about the immediate onset of action we both feel (nobody wanted to believe me that I can feel a huge difference from thyroid within less than an hour of taking it).

This is very interesting, as I can feel the difference within an hour as well when taking T3!
It may be from non genomic action of T3 but it's only a guess

 

[Learner1]

@Iritu1021 Thank you for taking a stab at my questions. There are a lot of moving parts and my situation is very different than pattismith's, so I'm having trouble seeing what's actionable here. If you'd be so kind, can you provide any interpretation for me?

And how can I be tested for T1AM status?

I have a high blood pressure variant of POTS with A1 and M4 antibodies who we think came from EBV, am celiac, and have high thyroglobulin antibodies. ANA and other antibodies normal.

I also have MCAS, but histamine and tryptase are usually low, other markers are high. It acts up badly with IVIG, and keep it managed with C, B5, 5-MTHF, B12, ketotifen, fexofenadine, benadryl, zantac, boswellia, and curcumin.

Norepinephrine is normal. I take tyrosine to keep my dopamine normal. We monitor and I take iodine to keep it range. It bounces high or low, never seems to be in the middle. Lithium was normal when last tested 15 months ago.

Thyroid feels fine on my T3/T4 dosing. rT3 is low normal, and TSH has been below .1 for 6 years. I take tiny amounts of pregnenolone, DHEA, estriol, testosterone, and replacement dose hydrocortisone.

Its not ideal, but I function. But, I have osteopenia and am actively losing bone, even though I lift weights and do other things that should be good.

One thing that I found in investigating is TSH helps with bones, but though I've raised T4 dose from 0 to 137, and dropped T3 from 100 to 50, it hasn't budged. From what you're saying, I'd need to be below 1mcg T3 to make a difference in my TSH? My doctor doesn't think I'd function if we drop my T3 much lower.

So, I'm reading all of your info above, where you discuss histamine, norepinephrine, iodine, estrogen, T3/T4, and am not sure where to go.

What does someone do to investigate and decide what to do? I think you're onto something....

Thank you for any insight you can provide.

 

[sb4]

@Iritu1021 Just done reading quite a few of your blog posts and this thread. Very interesting. I have some questions. I see there is a gap of around 5 years where you posted on the blog, did you get well in this time, are you well now? How did you do it? Time release low dose T3?

@Learner1 I know it's yet another supplement but have you looked into K2 (mk-4). Heard people have had success for that in regards to bone mineralisation. Apparently the heavily marketed mk-7 one doesn't help bones.

 

[Iritu1021]

@Learner1, to my knowledge there is no commercial way right not to get tested for T1AM - outside of basic science research. Also blood levels might be meaningless, it's might be cerebrospinal fluid levels that might be playing the larger part and that might be true for everything.

I can't really advise anything to you, I can only share my own experience. Looking back retrospectively, I believe that being on high doses of thyroid has messed up my histamine receptor sensitivity. Oral iodine when I took me gave me a boost of energy but also raised my blood pressure and given me more vasodilation and POTS.

DHEA, cortisol and pregnenolone always made me feel worse when I was on thyroid, gave me a spacey feeling in my head. (DHEA worked years ago in my early stages before I ever started messing with my thyroid). The question you should be asking yourself is whether you really need this drugs or if you are treating your adoptive body responses to something else. Only you can know the answer to this based on how you feel.

I'm not saying that getting under 1 mcg would help - it's just something I read in the book by Kenneth Blanchard MD "Functional Approach to Hypothyroidism" and in this discussion I was just trying to link this paradox he described to trace amine levels but I don't have any scientific evidence to support it. You can get his book on Amazon, he explains in it how he was rehabilitating people who used to be on high doses of T3/T4 combo and it messed them up.

Being on T3 only or high doses of T3 is not something that many people with dysautonomia are able to tolerate, for me it always amplified my dysautonomia. I feel it's harder for us to tolerate thyroid shifts than for people who don't have dysautonomia. Tiny doses of T3 (combined with T4 if there is actual hypothyroidism present) might be changing something in T1AM metabolism through a more gentle approach but it is probably just one of many possible ways to alter T1AM/T3 ratio. But you need to have normal TSH before you can do it. Also, you need to examine how each of the hormones and supplements you are taking is playing into your overall picture and get rid of anything that you can do without. Body is an extremely complex system, it is constantly changing, always adopting. What was true two years ago might not be true today, what worked for another person online might not be true for you.

Interestingly, my bone density used to be abnormal my whole life (I first tested it in my late twenties and I later assumed that it was due to my Ehlers-Danlos collagen effect) but on the last scan it was read as normal for the first time. I'm almost starting to wonder if even my Ehlers-Danlos diagnosis itself is a myth, that my collagen is just another casualty in the overall metabolic chaos that I've been living in for years...

The only real advice I can give you is to follow your body's intuition, not science because the science doesn't yet really understand any of these conditions.

 

[Iritu1021]

@pattismith
This is from Wikipedia, so if you take into account TAAR, other undiscovered receptors and the direct effect on cAMP levels, then the plot thickens even more...

"3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor.[1][2] T1AM is the most potent endogenous TAAR1 agonist yet discovered.[3] Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output.[4] Wu et al. have pointed out that this relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.[3]"

By the way, what happens if you take T3 more than once a day? Why can't you tolerate it?

 

[Iritu1021]

sb4, I started the blog when I first developed fatigue and brain fog in 2010. At that time I was writing very primitive stuff from my current standpoint, mostly re-hashing well known causes of fatigue that I read about online (I deleted most of my old posts except for a few that still bring some traffic to my site). Then I lost interest in that blog but for some reason I could never fully let go of it. I guess I was waiting for when I finally had something interesting to say that hasn't been said yet

I got very illl in 2014 after I was put on combo Vyvanse and Armour to treat my fatigue, "ADHD" and Hashimoto's. (both T3 and stimulants act on TAAR receptors by the way). At first I thought I had adrenal fatigue, than I pursued POTS and EDS diagnosis, then experimented with all sorts of alternative thyroid theories. During that time I was neither in the mood, nor had the cognitive function to write.

I still have some room for improvement in my energy and motivation department but my brain fog has cleared and I feel a lot more like my normal self - so I'm now getting more into "reflecting and sharing" mode.

 

[Ben H]

Hi guys,

V rarely do I post personal anecdotal stuff but it may fit in here, certainly on the other thyroid thread by @pattismith I think.

I'm severe borderline v severe some days now (totally bedridden, worse on my borderline days etc) but back when I was moderate, I tried a dose of Armour Thyroid.

It was one of those, ‘what the heck’ moments and I knew t3’s role in metabolism but my extensive thyroid labs, including rt3 and concurrently ratio was good. My t3 was infact upper range.

Anyway, within an hour or 2 of taking half a grain of Armour Thyroid, (4.5mcg t3, 19mcg t4) the huge lactic acid feeling in my arms and legs went away, felt ‘light’ (in retrospect just normal) and I went from 30-60% health in those 2 hours. It was incredible. Literally like a switch.

Lasted 2 days. Never could replicate again at all kinds of different dosages, straight t3 etc.

I have pondered so so much about this, what I have come up with ties in with Julia Newtons research and t3 and AMPK:

Newton: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

T3 AMPK- https://www.ncbi.nlm.nih.gov/m/pubmed/18703632/

(Basicallly that it temporarily normalised some or all of the issues mentioned in Julia Newtons study).

It may be a total crock and doesn’t seem to fit with Chris Armstrong’s theory I don’t think. But it makes some sense to me.


B

 

[pattismith]

@pattismith


By the way, what happens if you take T3 more than once a day? Why can't you tolerate it?

If I try to take a second dose of T3 when the symptoms are going back, it doesn't work, and I feel worse. Not hyperthyroid, just the usual symptoms that go worse.
I am now trying to take smaller dose (3.1 mcg is the smaller I can) and to change the rhythm of intakes (now I'm doing every 27 hours)

 

[pattismith]

Hi guys,

V rarely do I post personal anecdotal stuff but it may fit in here, certainly on the other thyroid thread by @pattismith I think.

I'm severe borderline v severe some days now (totally bedridden, worse on my borderline days etc) but back when I was moderate, I tried a dose of Armour Thyroid.

It was one of those, ‘what the heck’ moments and I knew t3’s role in metabolism but my extensive thyroid labs, including rt3 and concurrently ratio was good. My t3 was infact upper range.

Anyway, within an hour or 2 of taking half a grain of Armour Thyroid, (4.5mcg t3, 19mcg t4) the huge lactic acid feeling in my arms and legs went away, felt ‘light’ (in retrospect just normal) and I went from 30-60% health in those 2 hours. It was incredible. Literally like a switch.

Lasted 2 days. Never could replicate again at all kinds of different dosages, straight t3 etc.

I have pondered so so much about this, what I have come up with ties in with Julia Newtons research and t3 and AMPK:

Newton: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

T3 AMPK- https://www.ncbi.nlm.nih.gov/m/pubmed/18703632/

(Basicallly that it temporarily normalised some or all of the issues mentioned in Julia Newtons study).

It may be a total crock and doesn’t seem to fit with Chris Armstrong’s theory I don’t think. But it makes some sense to me.


B

Ben, the improvement you got from your thyroid hormons was the same I had from T3, just that my light/normal feeling lasted longer (8 hours), and was more repeatable.
The links you put are really interesting to me, as the phosphorylation produced by Thyroid Hormons seems to me a non genomic TH action according to my last reading (which means it is not caused by binding of TH on cells' nuclear receptors), and these non genomic actions/phosphorylations might explain why we can feel such a rapid effect from T3.

I am currently trying to read this book, he has a section about this topic, but it's a bit hard for my damaged and unstable brain!

http://library.umac.mo/ebooks/b28356354.pdf

I will read carefully your links, it is shorter, I may have a better chance to understand something out of it

 

[Iritu1021]

Wow, check out what just fell into my lap as I went to look up Ben's article online: T1AM induces hypothalamic vasodilatory response!

https://www.ncbi.nlm.nih.gov/m/pubmed/28368510/?i=1&from=t1am metabolism rodents

That must be what I was feeling with my POTS-type response... So I must have been raising thyroid and pushing my T1AM levels up but for some reason I couldn't handle them... That's why "the sweet spot" Ben's talking about is so impossible to maintain through exogenous means... I do know what you mean, Ben!

 

[Learner1]

This is fascinating. Can't wait to read through he 396 page thyroid book @pattismith shared! Thanks @Ben H for your articles, too!

I'm a visual person - would really like to see flowcharts of how this all works...

@Learner1 I know it's yet another supplement but have you looked into K2 (mk-4). Heard people have had success for that in regards to bone mineralisation. Apparently the heavily marketed mk-7 one doesn't help bones.

I'm using a nutrient tracker and get 500% of the DV in my diet, and I take a K2 MK4 supplement, along with calcium, magnesium, boron, strontium and vanadium. And estriol.

Interestingly, my bone density used to be abnormal my whole life (I first tested it in my late twenties and I later assumed that it was due to my Ehlers-Danlos collagen effect) but on the last scan it was read as normal for the first time.

That's fantastic! What changed it? Is like to see a diagram of all the interactions of biochemistry in forming and dissolving bone. I know that like you, others have successfully regained lost bone without resorting to Fosamax, etc.

DHEA, cortisol and pregnenolone always made me feel worse when I was on thyroid, gave me a spacey feeling in my head. (DHEA worked years ago in my early stages before I ever started messing with my thyroid). The question you should be asking yourself is whether you really need this drugs or if you are treating your adoptive body responses to something else.

Yes, well, I had stage 3 uterine/ovarian cancer, and lost my ovaries, which was part of what triggered my ME/CFS, so yes, you could say I'm treating my body responses to this.

I was absolutely miserable until we did a DUTCH (dried urine test of comprehensive hormones) which was extremely helpful in balancing my hormones so I can function. My doctor and I wanted my hormones stable while we work all of my other issues, and I don't feel like I have any hormone problems.

I have hyper POTS which developed POTS AFTER I got ME/CFS, so it didn't predate my thyroid problems. The T3/T4 keep me functioning.

Being on T3 only or high doses of T3 is not something that many people with dysautonomia are able to tolerate, for me it always amplified my dysautonomia. I feel it's harder for us to tolerate thyroid shifts than for people who don't have dysautonomia. Tiny doses of T3 (combined with T4 if there is actual hypothyroidism present) might be changing something in T1AM metabolism through a more gentle approach but it is probably just one of many possible ways to alter T1AM/T3 ratio. But you need to have normal TSH before you can do it. Also, you need to examine how each of the hormones and supplements you are taking is playing into your overall picture and get rid of anything that you can do without. Body is an extremely complex system, it is constantly changing, always adopting. What was true two years ago might not be true today, what worked for another person online might not be true for you.

I agree about reviewing what one is taking every so often. Right now, my body needs a lot of everything. My regular labs support this, unfortunately. I have been very ill, but function better than I should due to looking for abnormalities and patching the holes while working the big issues.

Also, you'd commented on IVIG. It has helped improve my POTS. My ME/CFS specialist has me on an autoimmune dose to see if we can beat back the autoimmunity.

@Ben H Would taking AICAR, NAD+, AMP, or creatine monophosphate help? I've been experimenting with oral an IV NAD+ and have heard good things about AMP IVs from my doctor. I also found this...

https://www.sciencedirect.com/science/article/pii/S001457930300560X

 

[Iritu1021]

It looks like T1AM also acts as muscarinic receptor antagoinst. I told you before that I have "profiled" my muscarinic receptors as whacked. It looks like Laurino's team in Florence is the main one that studies it.

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors.
Laurino A1, Matucci R1, Vistoli G2, Raimondi L3.
Author information
1
Dept. of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy.
2
Dept. of Pharmaceutical Science, University of Milan, 20100 Milan, Italy.
3
Dept. of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy. Electronic address: laura.raimondi@unifi.it.
Abstract
3-iodothyronamine (T1AM) is a trace amine suspected to derive from thyroid hormone metabolism. T1AM was described as a ligand of G-protein coupled monoaminergic receptors, including trace amine associated receptors, suggesting the amine may exert a modulatory role on the monoaminergic transmission. Nothing is known on the possibility that T1AM could also modulate the cholinergic transmission interacting with muscarinic receptors. We evaluated whether T1AM (10nM-100μM) was able to i) displace [3H]-NMS (0.20nM) binding to membrane preparations from CHO cells stably transfected with human muscarinic receptor subtypes (M1-M5); ii) modify basal or acetylcholine induced pERK1/2 levels in CHO expressing the human muscarinic type 3 receptor subtype by Western blot iii) modify basal and carbachol-induced contraction of isolated rat urinary bladder. T1AM fitting within rat muscarinic type 3 receptor was simulated by Docking studies. T1AM recognized all muscarinic receptor subtypes (pKi values in the micromolar range). Interacting at type 3, T1AM reduced acetylcholine-increased pERK1/2 levels. T1AM reduced carbachol-induced contraction of the rat urinary bladder. The fenoxyl residue and the iodide ion were found essential for establishing contacts with the active site of the rat muscarinic type 3 receptor subtype. Our results indicate that T1AM binds at muscarinic receptors behaving as a weak, not selective, antagonist. This finding adds knowledge on the pharmacodynamics features of T1AM and it may prompt investigation on novel pharmacological effects of T1AM at conditions of hyper-activation of the muscarinic tone including the overactive urinary bladder.

 

[Iritu1021]

@Learner1, yes if you don't have natural hormone production than of course your situation is different. That's why I'm afraid to advise - I think we're all in different quadrants and adaptations but with the same original triggers. I took thyroid for a very long time because it was the only thing that kept me functional, even at the expense of severe side effects, there was just no way to get off until I was ready.

It seems that one thing we all share in common - you, me and pattismith is that we all got screwed up by the major perturbations in our ovarian hormones, for me it was pregnancy and pattismith mentioned puberty as the first trigger.

 

[Learner1]

That's a good point. Also, I've heard of several cases changing for good or bad with pregnancy.

 

[sb4]

It looks like T1AM also acts as muscarinic receptor antagoinst. I told you before that I have "profiled" my muscarinic receptors as whacked. It looks like Laurino's team in Florence is the main one that studies it.

That study is very interesting. When you say your muscarinic receptors where whacked, do you mean they had antibodies against them or where they not responding in some other ways?

I am interested in the T1AM angle as I think a lot of my symptoms (particularly POTS stuff) can be traced back to muscarinic receptors and particularly M3.

 

[Iritu1021]

@sb4 - not only I'm pretty sure that I have whacked muscarinic receptors, I also feel that I know with reasonable certaintly that it's specifically M3 receptor (the one they specify in the article) that is abnormal because when I took tiny doses of fluoxetine I got opthalmoplegia from it (loss of eye accommodation). I couldn't switch between near and far vision for a couple weeks even after I stopped. Fluoxetine has a weak binding affinity to muscarinic receptors, so for such small dose to affect me so strongly there must have been some underlying issue going on...

When I was taking T3/T4 combo I noticed that I would get intermittent ptosis (droopy eyelids) which looked a lot like mild myasthenia gravis. My "eye size" was pretty reflective of how I felt.

I vaguely remember my POTS specialist mentioning that I had some nonspecific mild abnormalities on my acetylcholine sweat test but he didn't seem it was the main cause of my problem. I never pursued the antibody testing for my POTS so I don't know if there was another reason for that but T1AM explanation really fits with my overall thyroid experience and its "double-edge" sword.