Why T4-only Treatments Do Not [i][always][/i] Work (Why We Can’t Dose by TSH and Why We Need T3)

[Clutter]

Although it is true that T4 only treatment doesn't work for everyone, it does work very well for the majority of people once they are optimally dosed and underlying vitamin and mineral deficiencies have been corrected. There are a significant minority who don't do well on T4 only, however, and they will require the addition of T3 to feel well.

tiredthyroid.com/blog/2014/...

[marmaris]

That's a very interesting article Clutter and well explained in a kind of simpleton manner. I wonder what many a doctor would make of it if you printed this out and put it in front of them? The mind boggles!

[Clutter in reply to marmaris]

Marmaris, I rather doubt most would bother to read the blog or the research referenced. In fairness, I doubt much reading can be done in 10 minute appointments. If any did, fewer still would put themselves on the line by deviating from CCG & BTA recommendations that Levothyroxine is the accepted treatment protocol unless an endo or other specialist recommends prescribing T3 or NDT.

[marmaris in reply to Clutter]

So true. Often I go with a list of things to point out and I always come away with half of them not being dealt with. Whilst you are sitting there you almost feel guilty as if you are taking up too much time. This is so unfair as we often have to wait months before an appointment as well. We are just another piece of their red tapes I am afraid to say, that is why it is so important to have this forum so that we can self help ourselves and others.

[shaws Administrator]

When our TSH reaches a level many doctors/endocrinologists say we are in 'normal' range and we feel anything but normal. They don't believe us when we say how unwell we still feel but are willing to prescribe other medications for the 'symptoms' rather than more or better thyroid hormones.

This is a comment from Dr Lowe.

"The studies he critiques show that two studied types of replacement therapies were ineffective for many patients. Other studies, which Dr. Lowe cites, also show that patients using T4-replacement have an increased incidence of other diseases associated with hypothyroidism, and increased chronic use of drugs to control the symptoms of persisting hypothyroidism and those of other disease."

web.archive.org/web/2010073...

I noticed that No.3 on Clutter's post above is quoted an article by Peter Warmingham, a Trustee of Thyroiduk.org.

This is another good article by Peter called the Myths of Hypothyroidism.

thyroiduk.org.uk/tuk/thyroi...

[HIFL]

I was on T4-only for several years, and I would say I was one who did "very well," as you said. I certainly didn't have the horrendous problems I've read from others. However, there were little things, like the mixing up of words when speaking, and needing more sleep than others, so I don't know if everyone doesn't need just a teeny bit of T3. I'm wondering if everyone shouldn't routinely be prescribed 1/2 grain or 5 mcg T3 with their T4. As that graphic illustrates, I don't see how you can attain truly normal values without adding T3.

[Clutter in reply to HIFL]

HIFL, Your experience shows the difference between Ok on T4 and optimal when T3 is added. T3+T4 has been the answer for me as, in addition to FT3 improving, the T3 calmed the adverse side effects I had on T4 only.

I'm not sure the addition of T3 is necessary for those who feel well on T4 only. Presumably they are converting sufficient T3 or they wouldn't feel well. For those who aren't doing well, I'm sure the addition of some T3 could be very beneficial.

[shaws Administrator in reply to HIFL]

So although you felt 'well' there were other little things that cropped up. For instance, the most T3 receptors are in our brains and every single receptor cell in our body (of which there are billions) requires T3, not T4. T4 has to be converted and sometimes not sufficiently. I think, when we have been quite ill, eventually given medication, we get to a state where we feel much, much better but when you think about it maybe not 'perfect' as before.

[HIFL in reply to shaws]

There are actually T4 receptors, and the brain is primarily a T4 organ. If you google "non-genomic thyroxine brain" you'll see a lot of studies on this topic. But agreed, I think the most you can get on T4-only is maybe 90%. Something is missing, but it may not be noticeable for years. We need that extra T3 to get to 100%.

[PR4NOW in reply to HIFL]

HIFL, I do not agree with your statement, 'the brain is primarily a T4 organ.'

"The thyroid hormone (L-triiodothyronine (T3), thyroxine (T4)) plays a critical role in cerebellar development. Circulating T4 preferentially crosses the blood-brain barrier through several amino acid transporters. Then, it is taken up by astrocyte to convert into T3, which is a bioactive ligand for nuclear thyroid hormone receptor (TR). Liganded TR regulates the expression of target genes that may play an important role in cerebellar development and function. Thus, thyroid hormone deficiency results in the change in neuronal excitability and aberrant neurotransmitter transport, which induces abnormal motor coordination, decreased locomotor activity, and increased anxiety. In addition to genomic action of the thyroid hormone, T4 alters actin polymerization and iodothyronine deiodinase activity in astrocyte through non-genomic pathway, which may also contribute to the normal brain development. Taken together, thyroid hormone regulates cerebellar development and plasticity through multiple signal transduction pathways."

ncbi.nlm.nih.gov/pubmed/233...

"The concentrations of T4 and T3 in the brain are controlled by very efficient regulatory mechanisms involving thyroidal secretion, transport to the brain, expression of deiodinases and, in the fetus, transplacental passage of thyroxine (fig 4). T3 equilibrates rapidly between the plasma, liver, or kidney pools, whereas the brain pool equilibrates more slowly. Therefore, when T3 alone is administered as a constant infusion, to thyroidectomized rats, the liver and kidney require lower doses than the brain. However, when T4 is administered, brain T3 is normalized at doses that result in relatively low concentrations in plasma or liver (55, 56). In addition, the brain T3 concentration is maintained within a narrow range under a wide range of T4 dosage, thus avoiding T3 excess."

thyroidmanager.org/chapter/...

I think T4 has a very important role in development that is yet to be fully understood but if the brain had no T3 I doubt it would function. Respectfully, PR

[HIFL in reply to PR4NOW]

You are misunderstanding what I said. In my very first statement, I said that I believe that some amount of T3, even if it's 1/2 grain or 5 mcg, should be taken with T4, because I do not believe someone can be truly "normal" without that bit of T3. So I'm a proponent of combo T4+T3 therapy.

When the topic changed to the brain's function, my opinion is that no one can take only T3 and have relatively normal brain function. While saying that may make the T3-only camp irate, my observation, from reading multiple different forum posts over the years, is that these people have an explosive temper. Interestingly, this is a feature of Graves' disease! Inability to think and remember is also a feature of T3-only, and also a feature of Graves'. People on forums complain of this all the time, but are often told that they just need more T3.

On the other hand, someone on T4-only can have relatively normal brain function, if they have the deiodinase enzymes that create T3 in the brain. So I'm agreeing with you that yes, T3 is essential in the brain, but it should come from conversion, not supraphysiological T3 doses.

This is from your post: "brain T3 concentration is maintained within a narrow range under a wide range of T4 dosage, thus avoiding T3 excess." This says that when someone takes T4, the body can adjust the conversion enzymes to keep T3 within that NARROW desirable range. When someone takes T3-only, that is impossible; they cannot avoid the excess, and it results in rage, and other cognitive dysfunction.

[cc120 in reply to PR4NOW]

Very interesting.

[queridalady]

this is really interesting Thank you

[cc120]

Very helpful.

[shaws Administrator]

I agree with PR4NOW and this is an excerpt:

Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3′,5′-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3′-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity.

ncbi.nlm.nih.gov/pmc/articl...

[HIFL in reply to shaws]

The last section of that article implies that T4 is more important in the brain than T3:

A Possible Direct Role for T4 in Brain: Are There Contexts in the Brain in Which T4 is a Direct-Acting TRα1 Agonist?

Several recent studies have led to the view that T4 exhibits non-genomic roles that do not require conversion to T3 (20) but which have not challenged the general view that T3, not T4, is the only direct, biologically relevant agonist for nuclear TR function. Our own experiments indicate that TRα1 has the potential to act as a dual sensor of both T4 and T3 (Amy C. Schroeder and Martin L. Privalsky, unpublished observations).

Although the effective concentration of T4 in the brain is difficult to determine, it is plausible that T4 levels are sufficient to induce activation of TRα1-regulated genes in the brain even in the absence of T3. We suggest that the normal mix of T4 and T3 in the brain may actually confer a mixed T4/T3 transcription response mediated primarily by TRα1, together with a more pure T3 response mediated primarily by TRβ1. Notably, mice in which both deiodinase 1 and 2 have been genetically ablated, and thus lack astrocyte deiodinase conversion of T4 to T3, display only very mild defects in their physiological with little to no neurological defects (27). If, as indicated by these knockouts, T4 is not absolutely required in its traditional role as a pro-hormone, the dominance of T4 to T3 in the circulation and transport into the CNS may instead reflect a novel role of T4 as a direct-acting hormone and this direct role may be helping to ameliorate the effects of the deiodinase knockouts in the CNS.

[PR4NOW in reply to HIFL]

"The last section of that article implies that T4 is more important in the brain than T3"

It doesn't imply that at all, it implies that T4 may have a direct role along with T3.

"We suggest that the normal mix of T4 and T3 in the brain may actually confer a mixed T4/T3 transcription response mediated primarily by TRα1, together with a more pure T3 response mediated primarily by TRβ1."

"Therefore, the precise role of T4 as a pro-hormone and whether T4 might function directly as an active hormone in the CNS, remain incompletely answered questions."

Given the statement above it is all conjecture at this point until we gain a deeper understanding of just what effect T4 has when it binds to a TR. PR

[HIFL in reply to PR4NOW]

Perhaps this is all a matter of semantics? Someone on T4-only should theoretically also have T3 from conversion (maybe not optimal, but they should have some level of T3). Someone on T3-only would not have any source of T4 (if they had a thyroidectomy or RAI). Given that receptors respond differently to T4 or T3 (quote below), but ARE designed to respond to T4, suggests the brain would function better with T4 replacement than T3. [T4-only -> T4 + T3; T3-only -> zero T4] For some patients, the problem may not be lack of T3, but not enough T4 to reach physiologically normal levels, because of a misleading TSH.

"These two different TR isoforms differ in their ability to respond to T4, with TRα1 generally exhibiting a much stronger response to T4 than TRβ1. We suggest that different cell types may modulate their relative ability to respond to T4 versus T3 by altering the relative abundance of different coactivators and corepressors that have distinct responses to T4 and T3, raising the possibility that T4 may be able to function as a direct-acting hormone agonist with TRα1 (Amy C. Schroeder and Martin L. Privalsky, unpublished observations)."

[Hidden]

Thanks for this post, so, would the TPOab antibodies I have make this harder for the FT3 to rise as well as being on a low dose of Levothyroxine? (note: my doctor says this is not Hashimoto's)

[Heloise in reply to Hidden]

youtube.com/watch?v=3_uaUXi...(Not working as expected?)

I think you do have hashimoto's.

[Hidden in reply to Heloise]

Thanks, so why do the GPs not say this is Hashimoto's? I had a goitre a few years ago and it went down within 6 weeks but still showed up on ultrasound. I can feel a few lumps on the front of my neck where my adam's apple is so does Hashimoto's cause these lumps but before caused the goitre? That doesn't make sense to me. The doctor in the video says it can cause infertility but my sex hormones have been checked and they're normal. I have no other autoimmune illness either.

[Heloise in reply to Hidden]

I think goiters come about when your thyroid is attempting to produce more T4.

This article is from the Stop the Thyroid Madness website and I also have the site map and you can choose other topics that can explain everything.

stopthethyroidmadness.com/g...

Check out the MTHFR gene under Issues Related. stopthethyroidmadness.com/s...

[cc120 in reply to Heloise]

MTHFR direct link: stopthethyroidmadness.com/m...

[Glynisrose]

There always seems to be this idea that T4 is OK for some people, who told you that? A doctor? T4 alone is less than useless long term. Doctors have a vested interest in prescribing it similar to anti=depressants.

[Clutter in reply to Glynisrose]

Glynis, several friends and my sister have been doing very well on T4 only for a number of years. They were very surprised to hear of the problems I had on it.

[Agapanthus]

As someone who has now tried T4 only (for 17 yrs), followed by a v short trial of T4/T3 (synthetic and I probably should have tried a longer trial), and 2 years on T3 only, I found the original article very interesting.

I must be a classic case as explained in article of not being able to continue on T4 long term without significant symptoms, and given ME/CFS diagnosis. Eventually I had high FT4 and low FT3 (only found out latter via private test).

I felt much worse on addition of a small amount of T3 though to the T4 (20mcg) and have been unable to quite understand the reason for that. I feel I should have given myself more time than the 6 weeks I took over the experiment in retrospect. The endo was willing to let me try T3 only so I went in that direction instead.

Attempts to add in some T4 again this summer over several months just led to large amount of hair falling out, hair stopping growing on my legs, and generally feeling unwell so I stopped the experiment and went back to T3 only.

I am thinking of perhaps trying out NDT in the Spring as that is the only combination I have not tried.

As for my brain function - well that's hard to judge, since I wasn't doing well on T4 only either, and at 62 I guess I am not surprised if there is a bit of slippage. Certainly I don't have explosive anger on T3 only, though as I did not have Graves I may have some Thyroid function left presumably re giving me some T4, but how much is anyone's guess.

[Glynisrose]

The majority of people cannot tolerate levo long term. I guess there must be spme but not the amount that doctors report.

[Clutter in reply to Glynisrose]

Glynisrose, given that doctors don't accept that there is a thyroid issue when bloods are 'normal' I'd say that Levothyroxine is over reported as satisfactory. How long is long term? 40 years long enough? Of course, the dose is optimal, not forced into a TSH range.

[bobsmydog]

Wow!

Just found this article and now I know why I have been feeling even worse on Levo than I was before treatment began. This all makes prefect sense to me now - thank you for posting this!