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-   -   Does reverse T3 block T3 receptors? (http://boards.straightdope.com/sdmb/showthread.php?t=702730)

tracer 09-19-2013 03:36 PM

Does reverse T3 block T3 receptors?
 
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?

Isilder 09-20-2013 04:43 AM

This web page has references to articles on the idea that rt3 antagonises t3


http://www.custommedicine.com.au/hea...-t3-dominance/

DSeid 09-20-2013 09:01 AM

Quote:

Originally Posted by tracer (Post 16681279)

... 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. ...

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?

dasmoocher 09-20-2013 09:25 AM

Quote:

Originally Posted by Isilder (Post 16682516)
This web page has references to articles on the idea that rt3 antagonises t3


http://www.custommedicine.com.au/hea...-t3-dominance/

I'd be careful with that reference:

Quote:

Reverse T3 has the same molecular structure as T3 however its three dimensional arrangement (stereochemistry) of atoms is a mirror image of T3 and thus fits into the receptor upside down without causing a thyroid response and thus preventing or antagonizing the active T3 from binding to the receptor acting as a metabolic break.
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):

Quote:

Reverse T3 dominance, also known as Wilson’s Syndrome, is a condition that exhibits most hypothyroid symptoms although circulating levels of T3 and T4 are within normal test limits.
Quote:

Treatment

<snip>

Our preference is to supplement with a combination capsule (thyroid conversion capsules) which contains selenium, zinc, chromium, Vit B6 and B12, iron, Vit D and iodine as they are all required by the 5-deiodinase enzyme responsible for proper T3 production while the chromium helps control insulin resistance which can also impead conversion.
Wikipedia:
Quote:

Wilson’s (temperature) syndrome, also called Wilson’s thyroid syndrome or WTS, is an alternative medicine concept which is not recognized as a medical condition by mainstream medicine.[1] Its supporters describe Wilson's syndrome as a mix of various common and non-specific symptoms which they attribute to low body temperature and impaired conversion of thyroxine (T4) to triiodothyronine (T3), despite normal thyroid function tests.
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:

Quote:

Many endocrinologists believe that reverse T3 (3,3’,5-triodothyronine) is only an inactive metabolite with no physiologic effect. This is an erroneous belief as this and other studies demonstrate that reverse T3 (rT3) is a more potent inhibitor of T4 to T3 conversion than propylthiouracil (PTU) which is a medication used to decrease thyroid function in hyperthyroidism. In fact, rT3 is 100 times more potent than PTU at reducing T4 to T3 conversion. Clearly demonstrating that rT3 not just an inactive metabolite, but rather a potent inhibitor of tissue thyroid levels. The authors conclude, “Reverse t3 appeared to inhibit the conversion of t4 to T3 with a potency which is about 100 times more than PTU…”
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.

dasmoocher 09-20-2013 09:51 AM

To late to edit, but I caught this in the quote I cited from their website:

Quote:

Many endocrinologists believe that reverse T3 (3,3’,5-triodothyronine) is only an inactive metabolite with no physiologic effect.
Reverse T3 should be 3,3',5'-triiodothyronine.

So a site that concerned with the critical difference between T3 and rT3 gets the nomenclature wrong.

Qadgop the Mercotan 09-20-2013 10:28 AM

Quote:

Originally Posted by tracer (Post 16681279)
Mrs. Tracer is currently going to a Naturopath for treatment of her hypothyroidism, because she was dissatisfied with her mainstream endocrinologist.

Then she should find another endocrinologist, not a quack.

KarlGauss 09-20-2013 11:52 AM

Quote:

Originally Posted by tracer (Post 16681279)
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.

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.

DSeid 09-20-2013 02:28 PM

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.

Good luck!

DSeid 09-20-2013 08:14 PM

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.
Quote:

Reverse T3 (rT3) did not compete for the binding of T3 to either class of binding sites.
The closest I can come to my question is this abstract which also informs to the op:
Quote:

Reverse triiodothyronine (rT3) is an iodothyronine produced mainly by enzymatic inner ring [5-]monodeiodination of thyroxine (T4). The 5-monodeiodinase (5-MD) enzyme is most abundant in skin, cerebral cortex, and placenta. In contrast to triiodothyronine (T3), which is the most active thyroid hormone, rT3 has little or no calorigenic or thyroid stimulating horomone suppressive activity. However, rT3 may exert other important functions, e.g., regulation of T3 production (from T4), by its ability to interact with and inhibit both type I and type II 5'-monodeiodinases. Some suggest that rT3 may influence brain development in the fetus. On the other hand, elevated rT3 levels may interfere with recovery from hemorrhagic shock. Serum rT3 levels are increased in systemic non-thyroidal illnesses except chronic renal failure. This increase is related to decreased type I 5'-MD activity and decreased metabolic clearance rate of rT3 in non-thyroidal illnesses. Serum rT3 levels is also increased in patients taking drugs such as amiodarone, propylthiouracil, dexamethasone, propranolol, and ipodate. This too is related to decreased activity of type I 5'-MD caused by the drug. High serum rT3, low T3, and low T4 are correlated with bad prognosis in systemic illness.

dasmoocher 09-21-2013 02:25 PM

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:
Quote:

Mechanism of action
Thyroid hormone receptors regulate gene expression by binding to hormone response elements (HREs) in DNA either as monomers, heterodimers with retinoid X receptor (RXR; which in turn is activated by binding to 9-cis-retinoic acid) or as homodimers. However TR/RXR heterodimers are the most transcriptionally active form of TR.[6]
In the absence of hormone, TR in complex with corepressor proteins bind to HREs in a transcriptionally inactive state. Binding of thyroid hormone results in a conformational change in TR which displaces corepressor from the receptor/DNA complex and recruitment of coactivator proteins. The DNA/TR/coactivator complex then recruits RNA polymerase that transcribes downstream DNA into messenger RNA and eventually protein that results in a change in cell function.
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.
Quote:

Abstract
Interactions of environmental pollutants with the thyroid endocrine axis have received much attention especially because thyroid hormones (THs) play a major role in mammalian brain development. In order to screen for compounds that act on the triiodothyronine (T3) signaling pathway, we developed a new reporter gene assay expressing luciferase under the control of the TH receptor (TR). PC12 cells expressing the alpha1-isoform of TR of avian origin were stably transfected with a luciferase gene controlled by the SV40 promoter, and enhanced by a four-spaced direct repeat (DR4) thyroid response element (TRE). The resulting PC-DR-LUC cells were used to optimize a T3 assay in multiwell microplates. This assay was highly sensitive (30 pM T3) and reproducible, and responded as expected to TH analogues. Several halogenated phenolic (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl) and phenol (pentachlorophenol, 2,4,6-triiodophenol) compounds suspected of being thyroid-disrupting environmental chemicals induced partial agonistic and/or complex competitive/uncompetitive antagonistic responses in PC-DR-LUC cells at micromolar concentrations. A cell viability test indicated that these effects were not related to cytotoxicity of the chemicals. These results suggest that the PC-DR-LUC assay could be a valuable tool for the large-scale screening for thyroid receptor agonists and antagonists in vitro, and for detecting thyroid disruptors in the environment.

DSeid 09-21-2013 04:26 PM

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.

Interesting stuff.

dasmoocher 09-21-2013 06:10 PM

Quote:

Originally Posted by DSeid (Post 16686369)
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.

Did you notice that one of the authors of this cite is IJ Chopra, who is the author of one of the cites I quoted from Isilder's link?

Mmm...wonder why they didn't use this paper of his on their website.

jharvey963 09-23-2013 01:19 PM

Also to consider: here is an article about Naturopathy from Quackwatch:

http://www.quackwatch.com/01Quackery...turopathy.html

The first sentence call Naturopathy "largely pseudoscientific".

J.

tracer 09-23-2013 01:32 PM

Quote:

Originally Posted by DSeid (Post 16682927)
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.

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.

Quote:

Let me guess ... the pure T3 supplements are sold by the Naturopath and not available in a regular pharmacy?
Thankfully, no. Supplemental T3, called Liothyronine, is only available by prescription.

tracer 09-23-2013 01:53 PM

Quote:

Originally Posted by DSeid (Post 16683953)
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?

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:
  • You're fat and lethargic
  • It's all because of your thyroid
  • But you still have symptoms even though you're taking enough T4 to bring your TSH levels within the normal range.
  • That's because your doctor hates you. He's not LISTENING!!
  • You should be using desiccated thyroid extract instead, because it's natural!
  • Here, let's help you find a doctor that hasn't been taken in by the evil Abbot Laboratories, and still prescribes desiccated thyroid.

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.

Qadgop the Mercotan 09-23-2013 02:14 PM

Quote:

Originally Posted by tracer (Post 16691075)
You should be using desiccated thyroid extract instead, because it's natural!

Dessicated thyroid is produced by Armour. Which leads me to the following...

Thyroid, Armour thyroid! What kind of folks take Armour thyroid?

Fat folks.


Sorry, that's all I got. :(

tracer 09-23-2013 02:26 PM

Quote:

Originally Posted by Qadgop the Mercotan (Post 16691162)
Dessicated thyroid is produced by Armour. Which leads me to the following...

Thyroid, Armour thyroid! What kind of folks take Armour thyroid?

Fat folks.


Sorry, that's all I got. :(

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.

dasmoocher 09-23-2013 02:43 PM

Quote:

Originally Posted by tracer (Post 16691075)
Something must have struck a chord with her, because she started reading books like Bowthorpe's Stop the Thyroid Madness, whose basic message was:
  • You're fat and lethargic
  • It's all because of your thyroid
  • But you still have symptoms even though you're taking enough T4 to bring your TSH levels within the normal range.
  • That's because your doctor hates you. He's not LISTENING!!
  • You should be using desiccated thyroid extract instead, because it's natural!
  • Here, let's help you find a doctor that hasn't been taken in by the evil Abbot Laboratories, and still prescribes desiccated thyroid.

Take this with the grain of salt (iodized?) a review on Amazon merits, but interesting:

Quote:

It's amazing what a company will do when its losing profits. Now that doctors are giving synthetic hormones instead of Desiccated Pig Thyroid (Armour) there is suddenly a "movement" to fight this...Hmmm. I have seen pharmaceutical companies do this before. Lobbyists starting fake online profiles, websites claiming the competition doesn't work etc. Do some research and you will find the source of "Stop The Madness" and it the Armour company.

DSeid 09-23-2013 02:50 PM

Quote:

Originally Posted by tracer (Post 16690968)
... 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. ...

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.
Quote:

The efficacy of T4 and its comparable efficacy to T3 remain unresolved issues. A large-scale, well-designed, placebo-controlled study directly comparing the efficacy T3 and T4 in SSRI nonresponders with major depression would address this important issue.

In conclusion, the database on thyroid hormone treatment provides mixed findings in studies, often with methodological limitations and inconclusive data. The strongest evidence is for an antidepressant augmentation effect of T3 in antidepressant nonresponders, but the use of T3 in other ways to accelerate and enhance antidepressant treatment, as well as the clinical utility of other hormones of the thyroid axis, require further study.
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.

tracer 09-23-2013 03:25 PM

Quote:

Originally Posted by DSeid (Post 16691291)
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!

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.

tracer 03-03-2014 03:38 PM

Quote:

Originally Posted by DSeid (Post 16691291)
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.

Sorry to have to bring this thread back from the dead, but:

I've found a study from March 2013 which implies that it is T3 -- not T4 -- which the hypothalamic-pituitary axis senses, and which lowers TSH levels.

DSeid 03-03-2014 04:30 PM

I can't say that I completely parse out what that article is saying but I do not read that as saying that elevated plasma T3 will feedback and suppress TRF and TSH like T4 does (by way of local conversion in the mediobasal hypothalamus by D2 into localized elevated active T3). It seems to be saying that without astrocyte specific D2 plasma T3 is still normal because other cells step up D2 production in the face of elevated T4.

The basic concept is still as stated
Quote:

This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary
The point was
Quote:

To determine the relative contributions of these D2 pathways in the feedback loop
Again, not an endocrinologist.

tracer 03-04-2014 06:48 PM

That's odd, because in the Introduction to that study, they state:

Quote:

Given that the TSHB and TRH genes are negatively regulated by T3 (and not T4), it is crucial that T4 be converted to T3 in order to activate the negative feedback mechanism.

DSeid 03-04-2014 07:28 PM

Local conversion of T4 to T3 by cells in the region of the brain, not elsewhere impacting plasma levels.

Like politics the T3 levels that matter are local, and regulated by local levels of deiodinases activiating T4 and deactivating T3. Most of the body's T3 is produced outside of the thyroid by D2 conversion of T4 into T3. D2 is mostly regulated by a feedback of local T3 levels (more local T3 downregulates it) and T4 induced ubiquitination.

Again, the cross talk that goes on between these deiodinases and other regulatory enzymes at tissue specific locations varies according to site and I cannot claim to have a very solid grip on the complexity of the systems and the levels of feedback. I undertstand just enough to understand that I understand only a small portion of how it works and to be skeptical of simplistic explanations, especially by self-appointed experts.

Again, my limited understanding is that T4 invokes an additional level of localized regulation and feedback control above that imparted by a T3 approach which to my read means less risk of adverse outcome.

FWIW and no more than that.

tracer 03-11-2014 06:32 PM

UPDATE: I think I've found the smoking gun!

First, there's this passage from Molecular Basis of Thyroid Hormone Action, page 93:

Quote:

In the studies of the ability of unlabelled hormones to compete with [125I]T3 for binding to the affinity purified receptor, the rank of competitive inhibition of [125I]T3 binding was T3 >= isopropyl T2 > T4 > reverse T3 (Fig. 23).
(Figure 23 is on the next page, and shows 6 pretty graphs.)

Then, there's this study from the 1977 Journal of Clinical Investigation, pp. 1230-1239, whose abstract contains this little gem:

Quote:

In incubations with serum-containing media, reverse T3 was an ineffective competitor for T[sub[3[/sub] binding, and had only 0.1 the inducing potency of 3,3′T2 (0.001 the potency of T3).
Both of these are based on animal studies, but if humans behave like the rest of class mammalia, it appears that the T3 Receptors have 1000 times as much affinity for T3 as they do for Reverse T3. In other words, it reqires a T3-to-rT3 ratio of 0.001 or lower (i.e. 1000 times as much rT3 as T3) before the number of receptors binding to T3 is cut in half.

And normal blood concentrations of total T3 are 2-18 times HIGHER than blood concentrations of Reverse T3.

So even if Reverse T3 is a T3 antagonist, it's a pretty darned weak one.


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