Mrs. Tracer is currently going to a Naturopath for treatment of her hypothyroidism, because she was dissatisfied with her mainstream endocrinologist.
The Naturopath has her on a regimen of pure T3 supplements. She is taking no T4 at all. The Naturopath claims this is because of a test for serum Reverse T3 levels she had her take, which indicated that her Reverse T3 level was too high. (T4 can be turned into either T3 or Reverse T3 by various deiodinase enzymes found throughout the body.)
According to this Naturopath – and I’ve seen this same claim repeated on a buttload of alternative medicine websites – Reverse T3 is actually a T3 antagonist. That is to say, it blocks the T3 receptors, preventing the (normal, bioactive) T3 from doing its thing.
I asked if she could point me to a peer-reviewed journal article that could back up that claim, and she says she knows of one, but “it would be better if I were to search around on my own” so that I could also read all the stuff on those hypothyroidism-sufferers websites out there.
Well, I’ve searched around on my own, and I’ve found site after site repeating the “reverse T3 blocks T3 receptors” claim, but NO actual reference to the peer-reviewed medical literature in support of this claim.
So:
Is there actual evidence out there that reverse T3 acts as a T3 antagonist? If so, where?
I am not an endocrinolgist but this response is diagnostic of bullshit.
Never heard of anything like that and trying to dig myself the closest I get is evidence that such is likely NOT true. Old article but shows that giving reverse T3 did nothing to effect thyroid function.
No link on that complementary medicine site Isilder links to supports the claim either. It is just stated.
Let me guess … the pure T3 supplements are sold by the Naturopath and not available in a regular pharmacy?
T3 and rT3 do not have the same structure. Both are triiodothyronines but are not mirror images. T3 has two iodines on its inner tyrosyl (?) ring and one on its outer; rT3 has two iodines on its outer ring and one on the inner. Not the same structure.
More red flags (for me, at least):
Wikipedia:
Sounds like this site wants to sell you some supplements–thyroid conversion capsules.
I was going to look at this reference they list:
A study of extrathyroidal conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro. Endocrinology;101(2):453-63. Chopra IJ
But it’s from 1977 and you need a subscription to view it and there’s no abstract on PubMed or the Endo site.
This is their summary:
Inhibiting the conversion of T4 to T3 is not the same thing as rT3 acting as a thyroid hormone receptor antagonist. An antagonist would block the binding of T3 to the receptor. In theory, there is less T3 bound to its receptor in both cases, but the mechanism is different. In one case less T3 available to bind and in the other T3 is blocked from binding.
If her reverse T3 levels are truly elevated, it suggests that rather than being hypothyroid, she more likely has what’s called ‘sick euthyroid syndrome’. Basically, that is a state of (usually mild) functional hypothyroidism found in people suffering from non-thyroidal illness, e.g. states of inflammation, infection, malignancy, and even things like depression.
The “genuine” hypothyroid state is characterized by depressed reverse T3 levels.
It seems likely that tracer already suspects that this Naturopath is a quack and is merely doing due diligence. What he can do about that, I don’t know.
tracer if you don’t mind my asking, what did your wife find so dissatisfying about her mainstream endocrinologist? Was he trying to tell her that her low energy was not likley caused by low thyroid and suggesting she look for another cause?
To those who know about thyroid metabolism here …
So what does rT3 do? I understand that it is produced as regular T3 is made from T4 peripherally, usually in about equal amounts. And that that ratio changes in states like depression, sudden change in activity, caloric or carbohydrate restriction, illness, certain medication usage, so on. (Thus rT3 being elevated with normal range TSH and T4 and T3 in those states sometimes). To dismiss it completely as an inconsequential byproduct of regulating the very active T3 with a metabolically inert coproduct seems likely to be missing something, at least to me. Why make something inert in equal amounts instead of just making less in the first place? I see no evidence of its being a partial or weak antagonist but such is not completely an irrational thought - if it is only 1% as active and it binds to the same receptors then it blocks those receptors from being triggered by T3 with something less potent … But there is no evidence that such happens, some that it does not, and it seems like a crude hypothesis that makes little sense. (You activate T4 into T3 to get the bigger bang of the more active T3 form … why make something that goes the other way at the same time? Less sense than even making something completely inert.) Does it do something else in the body that T3 does not? I can’t find anything on what its unique function might be. If any.
I can find something that seems to suggest that there are specific rT3 receptors. And that rT3 is higher in the 2 weeks after birth before coming down to more typical levels. Both of these seem to suggest that it does something … but what?
In any case tracer the importance of elevated rT3 may be more as a marker that there is something else other than hypothyroidism going on that may need to be addressed more than what form of thyroid hormone will be more effective.
Trying to satisfy my curiosity about specific rT3 receptors (to little avail) I have also found this (and others like it) that further demonstrate that rT3 is NOT an antagonist to T3 - it does not bind to the same receptors much so therefore cannot block them.
The closest I can come to my question is this abstract which also informs to the op:
It seems there could be a simple experiment to determine whether rT3 acts as a thyroid hormone receptor antagonist.
There are ways of measuring the activation/repression of a cell signaling pathway by agonists/antagonists. A common one is called a dual luciferase reporter assay.
A DNA construct containing the response elements of a pathway specific transcription factor(s) along with a reporter gene is introduced into a cell.
Wikipedia for Thyroid Hormone receptors:
A thyroid hormone luciferase reporter assay contains the thyroid hormone response elements and uses luciferase as the downstream gene that is transcribed into mRNA by activation.
The amount of luciferase protein made by the transfected cell is positively correlated with activation by receptor agonists and is measured by providing a substrate, in this case luciferin, and quantifying the amount of chemiluminescence produced. The more activation, the more chemiluminescence produced.
The simple experiment would be to measure the amount of activation by an agonist such as T3 and then see if prior and/or co-treatment with rT3 reduces this.
These reporter assays exist for thyroid hormone receptors (see abstract below, for example) and I’m sure this has been done before somewhere.
A new bioluminescent cellular assay to measure the transcriptional effects of chemicals that modulate the alpha-1 thyroid hormone receptor. Toxicol In Vitro. 2007 Sep;21(6):1197-205. Epub 2007 Apr 14.
Jugan ML, Lévy-Bimbot M, Pomérance M, Tamisier-Karolak S, Blondeau JP, Lévi Y.
Lots of techniques … here’s another approach that shows there are specific rT3 receptors that are different than T3 receptors and that rT3 does not bind well to T3 receptors. So the exact claim made made the Naturopath is provably untrue.
OTOH … rT3 does feed back on the deiodinase enzymes that convert T4 into T3 and rT3 and on the ones that get rid of itself and other thyroid hormones, all apparently variably active in different local areas according to local factors.
Having read a bit more now the issue/debate does seem to be over how to handle the referenced euthyroid sick syndrome. Apparently the mainstream consensus is that neither T4 nor T3 should be given and there is a minority opinion that one or the other should be as T3 levels is certain target tissues are low, and of that group some believe that T3 is the way to go.
Interestingly, that article lists other journal articles that have reference it, and one of them is [url=http://www.eje-online.org/content/153/3/429.full Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats]. Whose title implies that rT3 somehow inhibits the D2 deiodinase enzyme, which is one of the two enzymes that can trn T4 into regular (non-reverse) T3. This is different from blocking the T3 receptors, but it does imply a lowered T3 production.
Thankfully, no. Supplemental T3, called Liothyronine, is only available by prescription.
Mrs. Tracer was diagnosed with hypothyroidism a couple of years back, by a mainstream doctor. (Her TSH levels were abnormally high, which is a classic sign of hypothyroidism.) Subsequent bloodwork revealed the presence of anti-TPO antibodies, which is pretty much proof positive of Hashimoto’s Thyroiditis (the most common cause of hypothyroidism in the developed world).
Her doctor started her on the smallest available dose of pure synthetic T4 (levothyroxine). To keep the dose even lower, he told her to take it on the weekdays and skip taking it on the weekends. She said she could feel the difference between the days when she was taking it and the days when she wasn’t, but had to twist her doctor’s arm to get her on a consistent daily dose.
Then, she started … reading up on hypothyroidism. There wasn’t a lot her doctor was telling her, so she fell back on the easiest, widest, quickest source of information she could find. Namely, Internet searches and asking around. There, she discovered a whole community of people (mostly other women) who whined incessantly about how awful their lives were and how no one was listening to them, including those awful mainstream doctors they’d been seeing. (I’m guessing. She didn’t actually share most of this information with me.) Something must have struck a chord with her, because she started reading books like Bowthorpe’s Stop the Thyroid Madness, whose basic message was:
[ul][li] You’re fat and lethargic[/li][li] It’s all because of your thyroid[/li][li] But you still have symptoms even though you’re taking enough T4 to bring your TSH levels within the normal range.[/li][li] That’s because your doctor hates you. He’s not LISTENING!![/li][li] You should be using desiccated thyroid extract instead, because it’s natural![/li][li] Here, let’s help you find a doctor that hasn’t been taken in by the evil Abbot Laboratories, and still prescribes desiccated thyroid.[/li][/ul]
Mrs. Tracer is quite overweight, so it’s entirely possible that a T4 dosage that would be adequate for an average woman wouldn’t be enough for her. But again, her TSH levels were now down within the normal range, so her doctor refused to increase her dosage – or add any T3 into the mix – despite the fact that she still felt lethargic. So she found a real endocrinologist, but this endocrinologist also dragged her feet when it came to adjusting her T4 dosage. So she found another endocrinologist, who was willing to ramp up her T4 dosage. But this second endocrinologist believed in never, ever, ever giving any of her patients any T3 for any reason.
So, having exhausted the endocrinologists in the area, she branched out in her quest to find a doctor who would LISTEN!! to her. That’s how she found this Naturopath.
To this day, she is convinced that just about every mainstream endocrinologist out there hasn’t been keeping up with the latest developments in thyroid research, and are thus pretty much useless when it comes to getting the treatment she wants.
Is that a parody of one of them thar newfangled TV commercials? I can’t keep up with everything you kids watch these days. Now get off my lawn!
<nitpick>
While desiccated thyroid was originally produced by the Armour meat packing company, they are no longer in that business. The Armour Thyroid brand name is now owned by Forest Labs.
</nitpick>
And to be fair, the USP standards for desiccated thyroid extract are considerably stricter today than they were thirty or forty years ago. It used to be only that the iodine level had to be within 15% of some target value. Now, the actual measured T4 and T3 levels have to be within 10% of a target value.
Which was noted by dasmoocher in his/her first post as being possibly true from a linked abstract: it does seem to be true that rT3 feeds back on the deiodinase enzymes. And that rT3 likely has other effects that are currently not well elucidated. (Those specific rT3 receptors are doing something, even if we do not know what.)
So again, the Naturopath’s claim is false but the idea that high rT3 may reduce the efficiacy of T4 supplementation has some reasonable theoretical basis.
That said it seems that the bigger significance of high rT3 is as a marker: it is high for a reason. What is causing it? It is established, for example, that the high rT3, low normal T3, normal T4, normal TSH state (euthyroid sick) associated with depression resolves upon successful treatment of the depression. Whatever other functions rT3 serves may, for all we know, be adaptive in the context of those other causes.
As previously cited above, it is established that neither T3 or T4 is useful in the euthyroid sick of serious systemic illness and may even be harmful.
There is some research I can find on using T3 as an augmenting agent for medication resistant depression which shows that it may be helpful, but no good comparison with plain T4.
Personally I’d be wary of a pure T3 approach. (Again, duly noting I am not an endocrinologist.) It is harder to overshoot the mark on T4 because if too high it feeds back on the hypothalamic pituitary axis (lowering TSH); T3 does not have that safety net.
I’d also personally run the other way from any one who told me that the study is out there but won’t share it with me saying instead that I should find it myself so I can read all the crap internet “experts” to inform myself. Especially if the claim as stated is wrong. This is not someone who knows wat they are speaking about and any correct medical decisions or advice, if any, are completely coincidental.
The best I can get out of after my little reading binge is that regulation of thyroid hormones is extremely complicated. It also appears that there are many practioneers both of the traditional medicine side and the alternative side who get very dogmatic in the face of what should be a fair amount of uncertainty. Shame that.
I also just found this site that you may appreciate! She also has a very nice collection of information pertinent to the T3 only rT3 issue that I wish I had found when I first got intrigued by your question … its reference list would have saved me a fair amount of time!
Oh, the parody is of the old hot dog commercial … you may not be old enough so get off our lawns! Enjoy.
Where that site gives references, it can be pretty decent … but overall, I trust tiredthyroid.com about as much as I trust all those natural-holistic-wellness sites out there.
On this page, for example (which is the same page containing the reference list you mentioned), the site claims that “rT3 does not block the receptor at all; neither rT3 nor T3 is in the receptor, that’s the problem” … and then fails to give any references to back up this rather important assertion.
