T3 is the Main Active Thyroid Hormone
T3 is the Main Active Tthyroid Hormone
T4 is a prohormone, or storage hormone. T3 is the only truly biologically active thyroid hormone.
However, from time to time someone airs an opinion that everyone needs to take some T4 (Levothyroxine, Synthroid or NDT), i.e. that it is critical to have some T4 medication.
So, in this blog 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; this genomic action of T3 IS the main action of thyroid hormone and the receptors are designed for T3.
However, T4 binds far less easily to the thyroid receptors in the cell nuclei. Researchers would say that T4 has a 'low affinity'. Even when 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 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 regulaton of cell function. 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.
Redundancy in the System
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.
One example of this is if the pathway for generating T3 within the cells through conversion is blocked, then the direct uptake of T3 via active transporters into the cells 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:
The body compensates to almost any combination of thyroid hormones when it has to.
If T4 is not present, the critical T3 genomic effects will continue and some effect of T3 will also occur non-genomically. Active transporters will also carry more T3 into the cells. This latter fairly recent finding changes a lot of understanding of the system. 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 - this is why I wrote 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. Those that think everyone should be taking some T4, look at studies that show how a normal balance of T4 and T3 work. 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. It is flawed logic and does not fit the science that we know already, let alone the science that has yet to be uncovered. This type of thinking is also frequently influenced because the people putting forth these views have themselves got well on T4/T3 or NDT (natural desiccated thyroid). There is a big danger in assuming that the solution that worked for you is correct for everyone else.
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. This is a known fact now. T3 itself has a non-genomic effect 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 them that T3-Only replacement generally works as well as T4 or T4/T3 (if it is necessary to use T3).
T4/T3 replacement is the 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 exploring T3-Only, and all the compensatory mechanisms will not be fully understood.
My perspective on the Thyroid Hormone Therapies 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 therapies 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:
However, T3-Only does work well, is safe, and is very effective when the other therapies 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.
Three Ways of Answering Why I and Others Do Not Need to Take Any T4 Hormone
So, based on all the above, there are three dfferent ways for someone on T3-Only to answer people who say that we need to be taking T4 with our T3:
1. "Why would I? I feel great on T3-Only, and feel ill when I add any T4" - this is the short answer.
2. "T3 is the active thyroid hormone. T4 is just a prohorme, 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.
3. 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 is more complete and it might help some of you if you wish to understand things at a slightly more detailed level. It may help you if someone raises the issue with you, and they appear to be genuinely open to discuss it (this is not my own experience with people that bring it up though).
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 prevailng view is that all patients only require T4 monotherapy.
I hope that you found this useful.
(Updated in February 2019)