T4 is a prohormone, or storage hormone. T3 is the only truly biologically active thyroid hormone.
People can be very well using T3-Only, or T3-Mostly, medication on its own.
People cannot be well on T4 medication if the T3 that is converted from it is too low.
However, from time to time someone puts forth an opinion that everyone needs to take some T4 (Levothyroxine, Synthroid or NDT), i.e. that it is critical to have some T4 medication.
In this post, I want to make it very clear what I mean by ‘T3 is the only truly biologically active thyroid hormone’.
Genomic and non-genomic action of thyroid hormones
Thyroid hormone receptors are present in the cell nuclei. T3 binds easily to these receptors. Researchers would say that T3 has a ‘high affinity’ to them. T3 affects gene transcription within the cell nuclei. This means that it is T3 that causes some genes to be active in fulfilling their purpose. It is by this process that the cells perform their function and produce whichever proteins they are designed to make. This is the main way in which thyroid hormone exerts its influence on our cells. The more T3, the faster this process occurs up to a certain limit. It is the main way in which metabolic rate is maintained.
Make no mistake here; the genomic action of T3 IS the main action of thyroid hormone, and the thyroid receptors are designed for T3.
T4 binds far less easily to the thyroid receptors in the cell nuclei. Researchers would say that T4 has a ‘low affinity’. Importantly, even if T4 does bind to the thyroid hormone receptors, its effects there are very weak indeed. We are not talking of a ratio of 1:4 here for the T4:T3 effect. T3 is at the very least 10 times more potent than T4 and probably a lot more than that (as T4 struggles to even bind to the nuclear receptors). The genomic effect of T4 is negligible compared to T3.
Now, in addition to this, there are thyroid receptors (integrin αvβ3 receptors), on the cell membranes. T4 can bind to these and exert non-genomic effects. These can be faster than the genomic effects, but they are not as powerful and do not result in the same regulation of cell function. Reverse T3 can also bind to the cell membrane receptors but cannot bind to the nuclear thyroid receptors.
It seems from the research that T3 can also bind to the cell membrane receptors and create these non-genomic effects but it may need to be at a higher concentration than normal to do this, i.e. as in people on T3-Only.
It is clear that the best combination for stability in the system, and to have it work as it is designed to do, is to have both T4 and T3. I have never argued that this is not the case. What I have argued is that you do not have to have T4 in order to be completely well, as T3 can replace the function of T4 if the situation requires it. It is important to be aware that some people cannot handle some, or even any, T4.
In addition to all the above, there is redundancy built into the system, i.e. the body compensates when needed.
This is very important. It also explains why it is NOT a good idea to get into ‘religious arguments’ about whether someone on T3-Only therapy should have to take T4 also. For example, if conversion from T4 to T3 is poor, the direct uptake of T3 into the cells, via active transporters, can be increased. This means more T3 will be taken into all cells and used there. Thus for people on T3-Only, more T3 than normal will enter all cells and will regulate cell function.
The body adapts and compensates when someone is on T3-Only. This is one reason I recently wrote the following blog post:
If T4 is not present, the critical genomic effects of T3 will continue, and some of the T3 will also act non-genomically at the cell membrane. Active transporters will also carry more T3 into the cells.
In the higher concentrations of T3 that exist when someone is on T3-Only therapy, the T3 will also bind to the cell membrane receptors, thus compensating for any lack of T4.
There is no loss of function due to having no T4 present. This is why people on T3-Only feel completely well when it is dosed correctly. It has to be dosed correctly though, as described in the Recovering with T3 book.
This is one of the big flaws in the arguments of people that say everyone has to have some T4. They look at studies that show how a normal balance of T4 and T3 works. Then they extrapolate this to a situation when someone might not have any T4, but they do not allow for any compensatory changes in the system. Their logic is flawed. It is often because they themselves got well using T4/T3 or NDT. There is always a big danger of assuming that whatever treatment worked for you will work for others.
Conclusions on the use of T3-Only, and on T3 vs T4 thyroid hormones.
So, what does all the above mean to those people on T3-Only?
Yes, we are missing the non-genomic action of T4. Does this matter? Almost certainly not. T3 in higher concentrations will compensate for what the T4 was doing.
We also know from pragmatic experience that people on T3-Only, even after thyroidectomy, feel completely well. That alone should prove it.
However, for those people who still are sceptical of this, you have to remember that there is redundancy in the system. Alternate active transporters are expressed to transport more T3 into the cells if that is more readily available than T4. T3 itself has a non-genomic effect at the cell membrane, and in higher concentrations will compensate for lack of T4.
This means that when studies are done that find particular functions of T4, it does not mean that those on T3-Only lack these. That is a wrong conclusion. On T3-Only the higher concentrations of T3 and the adaptation of the system will actually meet the need that the specific function of T4 was providing. Our system has compensatory mechanisms within it.
I have spoken with thyroid researchers at some length on this topic, and have not just read research studies and made my own conclusions.
It is clear to thyroid researchers that T3-Only replacement generally works as well as T4 or T4/T3 (if it is shown necessary to use T3-Only).
T4/T3 replacement is ideal, but if it does not relieve symptoms, it is of little value. There is no point in taking the ideal combination of medication if it leaves you feeling ill!
However, until the medical profession stops being opposed to T3 medication, there will not be enough proper research done that explores T3-Only treatment, and all the compensatory mechanisms will not be fully understood.
My perspective on the various thyroid hormone medications has never changed. I am in favour of using T4 replacement if it works well. If it doesn’t, T4/T3 or NDT should be tried. T3-Only is a good choice if the person remains sick on the other treatments and no other explanation can be found and fixed.
T3-Only is hard to dose, and it should be the therapy of last resort. I said this as soon as I opened this website in one of the early blogs:
T3-Only does work well, is safe, and is very effective when the other treatments have been shown to leave the patient unwell.
T3 is the main biologically active thyroid hormone. T4 remains, in essence, a pro-hormone with far less effect than T3.
I hope the above further clarifies my views on this subject. I have remained consistent with the above throughout the years and in my books.
When asked why I or others do not take any T4 medication, I have three ways of answering:
- “Why would I? I feel great on T3-Only, and feel ill when I add any T4” – this is the short answer.
- “T3 is the active thyroid hormone. T4 is just a prohormone, with weak, or negligible effects until it is converted to T3”. The typical answer I give, and the way I usually express it in my books. It is simple and accurate but does not include all the details and discussion.
- This blog post – the longer answer. It is more full and complete. However, most of the people that raise the T4 issue with me, tend to be quite argumentative and sometimes even aggressive in their opinions. They do not appear to be open to any answer that isn’t the one that they had to begin with. So, I rarely go to a deeper level.
This blog post might help some of you if a thyroid patient, or doctor, raises the issue with you, and they appear to be genuinely open to discuss it. Unfortunately, my own experience is that people are not open to discussing it.
Overall we need more research into T3-Only use, and how the body compensates in this situation. However, as I have mentioned, this is very unlikely to happen whilst the prevailing view is that all thyroid patients only require T4 monotherapy.
I hope that you found this useful.
(Updated in February 2019)