I've been doing a fair bit of reading and I see that the stance here is that rt3 is useless.
Maybe this will help someone.
A cell will have a receptor for T3 and RT3 can bind to it weakly (thanks Helvella, I have corrected it).
When you take too much T4 or you don't convert well, your protective system will upregulate DIO3 enzyme, which would degrade T4 into RT3 and also T3 into T2, making you more hypo.
That's why a balance between T4 and T3 is important and RT3 is not completely invalid especially if coming back high and you have symptoms. There are people which cannot take any T4. There is a reason for that. There is a lot of people, which have to reduce T4 containing meds and increase T3.
Also, rt3 absolutely hangs around for longer periods of time after a peak.
Just my two cents 😊
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A cell will have separate receptors for T3 and RT3.
The paper quoted below says that rT3 does not bind significantly to cell nuclear receptors. It does not have its own receptors. And its binding to T3 receptors is too weak to have an impact.
And that measuring rT3 has very little clinical utility.
First published online October 12, 2020
Clinical and laboratory aspects of 3,3′,5′-triiodothyronine (reverse T3)
David J Halsall and Susan Oddy
Abstract
Reverse T3 (3,3′,5′-triiodothyronine or rT3) is the third most abundant iodothyronine circulating in human blood and is produced by the inner ring deiodination of the pro-hormone thyroxine (T4). Unlike the more abundant and active metabolite T3, the measurement of serum rT3 is yet to find a routine clinical application. As rT3 binds weakly to the T3 thyroid nuclear hormone receptors, it is thought to represent an inactive end-product of thyroid hormone metabolism, diverting T4 away from T3 production. The analysis of serum rT3 has, up until recently, been measured by competitive radioimmunoassay, but these methods have been superseded by mass-spectrometric methods which are less susceptible to interference from other more abundant iodothyronines. Serum rT3 concentration is increased as part of the non-thyroidal illness syndrome, and by administration of common medications such as amiodarone which inhibit the metabolism of rT3. Serum rT3 concentration is also affected by genetic conditions that affect the iodothyronine deiodinases, as well as thyroid transporters and transport proteins. Analysis of rT3 can provide a useful diagnostic fingerprint for these conditions. rT3 has been shown to bind extra-nuclear iodothyronine receptors with a potential role in cell proliferation; however, the clinical relevance of these findings awaits further study.
Conclusion
The routine measurement of serum rT3 is yet to find an application in the clinical laboratory. Analysis is of value in the investigation of rare genetic syndromes such as thyroid hormone resistance α and suspected tumour syndromes such as consumptive hypothyroidism due to haemangioma; this service can be offered via referral laboratories, rather than general clinical chemistry laboratories. rT3 analysis is likely to be of value in further defining the non-thyroidal illness syndrome, and as to whether some patients may benefit from intervention. While rT3 does not bind to the nuclear thyroid hormone receptors, the discovery that rT3 may bind to extranuclear receptors may allude to a more active physiological role for rT3. rT3 may have a direct effect on tumorigenesis, and the role of NTIS on this process is intriguing. Based on current literature, there is no evidence to support the routine measurement of rT3 as an aid to guide thyroxine replacement therapy.
Also, rt3 absolutely hangs around for longer periods of time after a peak.
Regarding half-life, rT3 has a short half-life.
Besides having no known biologic function, it should also be noted that the half-life of rT3 in the blood is 4 hours. Compare that to T3’s half-life of 1 day and T4 at 5-9 days, and you will appreciate another reason why doctors avoid placing much emphasis on the rT3 level.
I think the main thrust of posts here is to say that regular rT3 testing benefits no-one except the lab operators. But that there are some, a few, circumstances in which it might be worth testing.
Of course, there might be other sources which take different views.
Would it be still correct to say that upregulated DIO3 could cause hypo issues though?
Also, half life wise, it depends how much rt3 is being made, meaning how big is the peak?
I think it is worth testing, if someone like myself has a non existent tsh, upregulated DIO3, I would benefit more t3 than t4 in that case and rt3 could show how bad that DIO3 activity is. Which normally is to prevent us from being overdosed of course. And this is why I believe it is very hard to find a balance on combo meds when we're not doing well on T4 only.
I also believe excess t3 can also cause hypo symptoms through DIO3.
"This conclusion is largely based on the evidence previously discussed that rT3 has very low affinity for the nuclear TSH receptors and is unlikely to compete with T3 for these receptors or for the deiodinase enzymes at physiological concentrations."
At physiological concentrations. The question is, what are physiological concentrations and in what environment our hormones work if we take exogenous hormones?
We create larger peaks by taking thyroid meds. We need more studies on this with different cohorts taking different meds.
Also, half life wise, it depends how much rt3 is being made, meaning how big is the peak?
If you imagine taking 100 units of T4 every day and that is keeping your blood levels steady..
And that is fully absorbed instantly when you ingest it.
Your blood T4 level shoots up to reflect that.
Then, say, 50% of that is converted to rT3 - again, instantly.
So you have 50 units of T4 and 50 units of rT3. (If you think of the units as being the number of molecules it makes some sort of sense.)
After four hours, rT3 will be at 25. After eight hours it will be 12.5. After 12 it will be 6.25. After 16 it will be 3.125. After 20 it will be 1.5625. After 24 it will be 0.78125.
Whereas the T4 you took today, even if it had a half-life of just one day, would only have dropped to 25. (And that is after 50% has already been converted to rT3!)
This is, of course, unrealistic in many ways. But I’m trying to emphasise that the short half-life is critical. The peak of rT3 will never be anything like as high and will fade away much, much faster.
And, yes, of course, if you plot it molecule by molecule, and consider the effects of each of the DIO enzymes, etc., my words are a gross over-simplification.
In my case I was taking 150 t4 and almost 40 t3 in one go. I assume that created a huge peak. Also, as we take t3 and increase it, I believe even more T4 will go into rt3 in some cases.
Even recently I tested my rt3 10 hours after a dose on 2.5 grains of Armour and 6.25 T4. My rt3 was 26 (range is up to 24). Pretty worrying.
I dropped Armour and additional T4, added a tiny bit of T3 and felt better. Unfortunately I measured my rt3 then in the morning, it was just under midrange.
Right now I increased t3 and didn't decrease Armour and tested Rt3 just 3 days ago to see what it does.
I'm not being frivolous with rt3 testing, it is actually costing me only 20 euro where I live 😀
I'm one of those people who can't take any T3 or any supplements that contain thyroid glandular. Even a medication like NP Thyroid or Armour makes my RT3 increase rapidly (from the lowest number shown in the range to the very top of the range in just 31 days. My last attempt at taking T4 had me in the emergency room on day 31. While Inability to convert T4 to T3 properly and issues with RT3 aren't hight common, for those of us who experience the challenge, it can be agony with very severe hypothyroid symptoms coming on rapidly.
That's awful. I didn't have such bad reactions to T4. Did quite well on Armour for a few years and then I stopped tolerating it, whether due to the ever raising T4 or cortisol, jury is still out. I think there are more people with conversion issues than we think. Up to 30% of human population have polymorphism. Obviously doesn't mean the gene defect is activated.
I'm one of those people who can't take any T3 or any supplements that contain thyroid glandular.
Just for the sake of clarity, might you edit the typo T3 to read T4 - RT3 can only be created from T4 so the typo might be confusing to some people (i.e. I'm not just being pedantic :))
The test is expensive and time consuming and I don’t think you even need to measure levels because you can safely assume RT3 will eventually become elevated if your meds aren’t working and you are feeling symptomatic.
" …. if someone like myself has a non existent tsh, upregulated DIO3, I would benefit more t3 than t4 in that case’
A non existent TSH and unregulated DIO3 will give no indication of whether you require T4 mono-therapy, T4/T3 combo or T3- only to achieve wellbeing. This is because all 3 deiodinases present in different tissues that control cellular activation of thyroid hormones, and are influenced not only by each other but differing physiologic conditions. For our meds to work efficiently it involves transport, signalling, excretion and the effects of genetic variation as well as T4, T3 and RT3 levels.
Obviously if you've been raising T4 level unrealistically high, it would be a fair assumed causative factor of elevated RT3 (or unregulated DIO3) but could equally be the result of chronic inflammation or iron deficiencies and will usually be a combination of many things. This is the argument for RT3 being irrelevant for testing but it is an extremely important hormone to help regulate the thyroid hormones from over stimulation of the tissues.
“I also believe excess t3 can also cause hypo symptoms through DIO3’
Yes, absolutely agree. It can impair meds from working and even after excess T3 levels are reduced it can take a long time for things to reverse because thyroid hormone effect systems in a bidirectional fashion, meaning it is not only the RT3 controlling thyroid meds activation/deactivation. Also RT3 is mainly bound to TBG serum binding proteins TBG (and TTE and albumin), leaving less room for thyroid hormones and more frees. A further proportion then risks being converted to further RT3 to eliminate the excess frees.
Basically think of elevated RT3 being the result of anything ‘unhealthy’ that is a level more than your body can tolerate, eg crash dieting, a long term excessively sedentary lifestyle with a processed/sugar laden diet, depression, severe trauma or infection . Or just life issues such as excess oestrogen that clogs the liver making all detoxification slow and inefficient. Common causes of high RT3 on this forum are often inadequate nutrinets/iron/cortisol issues in combination with wrongly dosed thyroid hormone replacement medication.
Regarding the half life of RT3, I think helvella refers to a healthy system?, as I understand RT3 can hang about a long time in some instances. It is usually eliminated from the body via excretion and conversion to inactive T2 mainly by DIO1, but some inducements of elevated RT3 can also impair these pathways, so raising RT3 levels higher and for longer. For example conversion of RT3 to T2 still needs adequate selenium and zinc often inadequate in hypo, and DIO1 will become naturally down regulated in the presence of elevated RT3. Also the liver is involved with getting rid of a large part of excess/old RT3 but hepatic function often slows inline with hypo symptoms.
This is just my personal experience. A while back I was having issues when on T4 only. I had been stable at around .50-1.0 TSH for a number of years. Then all of a sudden my TSH jumped to 3.1 back to 1.77 and then up to 2.293 (these were all at annual exams). TSH was all doc would order. I felt so unwell that I even told my husband I felt as though I were dying. I had a very combative discussion with my PCP and was finally referred to an Endo. This Endo upped my dose of T4 which did not help. Next she added T3 to my upped T4. Ok, I had a very good sweet spot like 6 months later where my FT3 was 3.9 and FT4 was 1.67. That lasted about two months and then I started feeling more and more fatigued and just not well. About 4 months later I ordered my own labs. FT3 2.7, FT4 1.72 (over range). Then3 months later another set of labs after doc reduced T4 some. FT3 3.4, FT4 1.95 (over range) and RT3 60.2 (way over range). I felt very unwell and severely fatigued. Endo decreased dose of T4 again and labs showed FT3 2.5, FT4 1.9 (over range) and RT3 51.6 (still way over range). It wasn't until I removed all T4 that I started to feel better. Once T4 was gone I did try to add small amount back in and my RT3 shot up immediately. So ended up on T3 only for two years. Then was referred to a different Endo and she would not prescribe T3 only as 'it causes heart attacks'. Anyway, I finally ended up with a dose of T3 of 25 mcg and Tirosint 75 mcg and have been on that particular dose since early 2019. Although I don't test RT3 regularly anymore just once in a while I find that it stays in range of 15-19 most of the time. I feel good at dose I'm at. No one can tell me what happened or why and no doc can explain why after finally starting T3 my trigylcerides finally are in normal range and why no more palps. They will not acknowledge that T3 actually had a good effect in my opinion. BTW the last Endo I had also tried to tell me I was addicted to T3! I personally think RT3 does affect a person, at least it did me.
That's super helpful, thank you for sharing.When you were over range on ft3 ft4, did you feel increasingly worst in terms of fatigue and other symptoms? I'm curious as to what other symptoms you had with these higher labs.
I think this issue is made even more complicated because there are so many different camps:
1. RT3 has no metabolic activity at all or very weak activity, it does not compete with T3 for cell receptors, it is an inactive by-product of T4 that is eliminated from the body within hours (most conventional medical sites and many HU forum members).
2. RT3 is more potent than anti-thyroid drugs and can make you fully hypothyroid unless you go on T3 only for at least 12 weeks to flush it out and make T3 able to bind to cell receptors again (STTM, many functional doctors in the US but quite a few in Australia, too, who advocate Cytomel or compounded T3).
3. RT3 itself is not a problem, the problem is DIO3 that converts T4 to RT3 (thyroid patients and authors Tania Smith (thyroidpatients.ca), Paul Robinson).
It is not easy to know what to think.
Some claim that the rise in RT3 after a strict diet is the reason so many people regain weight, and is the reason behind yo-yo-dieting where you lose 20 pounds and regain 40. Somehow, it seems metabolism is lower after a diet and there must be a medical reason for it related to decreased metabolic activity?
On the other hand, there seem to be countless reasons why RT3 could be high, so it seems a bit too easy to simply go off T4 for 12 weeks and all will be well. And, even if you manage to identify what caused high RT3 in the first place, what if you cannot completely eliminate it (eg. stress raising cortisol if you have a stressful job)? Will you have to stay on T3 only indefinitely or find a new job?
This is a subject where it feels like the more I read, the less I understand…!
Yes, but some claim the RT3 to T2 conversion can be impaired. What happens then? Some say T2 is an active hormone that we need, others that it has low metabolic activity so is a way for the body to get rid of T3.
And, if RT3 dominance is not a symptom of thyroid dysfunction, but rather extra-thyroidal conversion gone wrong, why is it only a problem in thyroid patients, as everyone depends on extra-thyroidal T4 to T3 conversion? It is often said that this condition was first discovered in critically ill ICU patients and known as ESS (euthyroid sick syndrome) or NTI (non-thyroidal illness). But nobody suggests treatment for such patients…the condition is expected to go away when they recover.
These are rhetorical questions, I know. But my main problem is: if this is a dysfunction that happens outside the thyroid gland, why would hypothyroid patients need treatment when euthyroid people don’t…?
Also, many known triggers for high RT3, like impaired glucose metabolism and inflammation, are found in lots of people outside the thyroid community. But I have never seen any medical advice on how to lower RT3 in euthyroid people, except the obvious (eat less sugar, reduce inflammation). Why would that not be enough in patients on thyroid hormone replacement?
I used to believe in the RT3 dominance theory. It offered a solution to every unsolved thyroid symptom. But then, the more I think about it, the more flawed the theory seems…one big reason being that nobody ever addresses what will happen if, after 12 weeks on T3 only, symptoms are still present…? Has no doctor treating RT3 dominance ever failed? Why are there no ’before and after’ success stories on the websites of those practitioners and clinics?
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