Sometimes 2 +2 does not equal 4 when dealing with thyroid hormones.
This blog post is relevant to those patients who are trying to feel healthier by increasing their thyroid medication, but find that this does not seem to work.
It also applies to those who are beginning to receive thyroid hormone treatment.
The typical pattern
I have frequently observed that, after an increase in thyroid medication, patients immediately feel a lot better. This can be more obvious when someone adds T3/Liothyronine. The individual is often convinced that this increase is going to be wonderful for them, and that they will now continue to feel so much healthier.
However, after 3 – 5 days, this initial benefit often disappears and they feel just as bad as they did before. Why is this?
This pattern is easy to understand when you realise that the conversion rate of T4 to T3 is not fixed – it is variable and regulated. I hope that this post will help to explain what happens.
Conversion from T4 to T3
Only unbound (free) thyroid hormones are able to enter our cells. Therefore, only Free T4 (FT4) can be converted to Free T3 (FT3). For the purposes of simplicity when I discuss T4 and T3 I will usually be referring to FT4 and FT3.
T4 to T3 conversion occurs within every cell of the body. Most of the T3 in the blood comes from conversion within the cell walls of the thyroid gland, liver, kidneys, peripheral tissues, and the gastrointestinal tract.
All cells depend on taking some T3 from the bloodstream and/or taking in T4 and converting it to T3. The cells vary substantially in their ability to convert T4 to T3 depending on what tissue they are part of.
This process of conversion requires the removal of an iodine atom from a T4 molecule, so it is referred to as deiodination. There are enzymes produced in certain tissues (cells of the body), called deiodinase enzymes. It is through the action of two of these enzymes (D1 and D2 deiodinase) that T4 is converted to T3.
The brain, pituitary, heart, thyroid gland and skeleton muscle (peripheral tissues) use D2 to convert T4 to T3. The liver, kidneys and thyroid gland use D1.
D2 is significantly more efficient in converting T4 to T3 than D1. However, D1 deiodinase is very important in the clearance of Reverse T3 (rT3) by the liver. The liver clears rT3 through the deiodination of rT3 into T2, then T1 and T0 (which is excreted within a day). In some people, genetic defects associated with these enzymes can hamper conversion from T4 to T3, and rT3 clearance.
The thyroid gland contributes about 25% of our circulating T3. This occurs through T3 production and T4 to T3 conversion within the thyroid. Consequently, the thyroid production of T3, and its conversion of T4 to T3, provides a large proportion of the available T3 in the body. Even if the thyroid gland produced no hormones of its own, it would still convert the T4 that is present in the blood that flows through it. The thyroid gland is like a little machine that sits in the blood flow, converting T4 to T3.
T4 to T3 conversion requires adequate amounts of the right deiodinase enzymes. These enzymes are heavily dependent on the mineral selenium in their construction. Consequently, it is important to have enough selenium in the diet or through supplements. The conversion process is also dependent on levels of B12, zinc, ferritin, and iodine.
D3 deiodinase enzymes convert T4 to Reverse T3 (rT3). Although rT3 itself only has a minor effect in reducing the level of D2 enzymes, it is a marker for problems. This is because when rT3 is high, there is likely to be a higher level of D3 enzymes. D3 enzymes prevent T3 from binding with receptors in the cell nuclei, i.e. they block the effect of T3. In some ways, rT3 can be seen as a ‘T3 blocker’, but it is really the D3 enzymes that are doing this.
The thyroid gland has TSH receptors within it. The thyroid uses TSH to regulate its production of T4 and T3. The thyroid produces less of its own T4 and T3 when TSH goes lower. The thyroid produces more T4 and T3 when TSH is higher.
Importantly, the thyroid also makes fewer D2 and D1 deiodinase enzymes when TSH is lower, and more enzymes when TSH is higher. So, the conversion rate of T4 to T3 within the thyroid gland is lower when TSH is reduced. The Conversion rate is higher with higher TSH. Researchers call the process of adjusting the level of deiodinase enzymes up-regulation (making more) or down-regulation (making fewer).
The takeaway here is that the more D2 and D1 deiodinase enzymes there are, the better the conversion rate from T4 to T3, i.e. more T3 is produced from conversion. The fewer D2 and D1 deiodinase enzymes there are the lower the conversion, i.e. less T3 is produced from conversion. This is the process that up-regulates and down-regulates conversion. So, the conversion rate is not fixed at all – it is variable and regulated.
Other tissues than the thyroid have TSH receptors too. Brown adipose tissue, found in various parts of the body also contains TSH receptors. This tissue will also up-regulate its deiodinase enzyme production with higher TSH and down-regulate it with lower TSH. The conversion rate from T4 to T3 will be adjusted in the same way as in the thyroid gland, i.e. less T3 will be produced from conversion with lower TSH, and more T3 will be produced with higher TSH.
According to thyroid researchers, is it likely that there are other tissues in the body with TSH receptors. The cells of the heart, fat, and bone are thought to have TSH receptors, and it is likely that more locations will be discovered over time.
Conversion from T4 to T3 is definitely not fixed at a certain level. It is variable and regulated.
I attach research references at the end of this post for those of you who wish to see even more detail.
So, that is the really technical bit.
What is interesting is how this information can be used and what it means to you!
What are the implications?
What happens if a patient adds more T4 medication when their TSH is not fully suppressed yet?
After an increase in T4 medication, the effect will be that the T4 accumulates to create a new higher FT4 level over the next couple of months. TSH is likely to fall slightly. It may only be a small change but it is often significant. Most of the reduction in TSH will happen over the first week or so because that is when the biggest rise in T4 will occur.
Until this change in TSH occurs, the patient will have more FT4 as a result of the increase in T4 medication, and this should produce more FT3. With a slight increase in FT3, the patient may feel an improvement in well-being. We know that FT3 is the active thyroid hormone and that research has shown that FT3 is the only laboratory test result that changes when symptoms adjust.
However, the lowering of TSH that inevitably occurs, will tend to induce a reduction in the rate of conversion of T4 to T3 (due to the effect on down-regulation of the deiodinase enzymes described above). The production of T4 and T3 by the thyroid gland will also reduce due to the reduction of TSH.
As mentioned above, the conversion rate is likely to be regulated by TSH in some other tissues. So there may be some lowering of conversion rate in other areas of the body.
Consequently, after a few days or a week of feeling better, the poor patient is often right back where they started and feeling poorly again.
Do you recognise that pattern?
What happens if a patient adds some T3 medication?
The same mechanism occurs when a little T3 is added alongside T4 medication. But the results can be even more pronounced.
When a thyroid patient begins to add T3 to T4 medication, the first thing that happens is that free T3 levels increase.
FT3 levels rise and the thyroid patient feels better! This is not a surprise, as T3 is the biologically active thyroid hormone. This improvement can last for 2 to maybe 7 days.
But the improvement is often not sustained. It is a top-up of T3 after all, so why shouldn’t it last?
The reason it frequently fails to last is due to the mechanism that I have explained above.
The lowering of TSH that comes with the increase in FT3, lowers the conversion rate of T4 to T3. Consequently, for those patients who rely on some T4 medication (or some natural thyroid medication, or some T4 from their own thyroid gland), adding T3 medication can create an initial great result, which is then followed after some time by lower conversion of T4 to T3. The circulating T4 thyroid hormone that you have just does not convert to as much T3 anymore. You have added extra T3, but you have lost some converted T3!
The net result is often a good improvement of symptoms followed by FT3 dropping to a level that is just as low as it was to begin with.
Some of you reading this may have added T3 thyroid medication and felt that increase of FT3, but then after some days, they may then have found themselves back where they started in terms of symptoms.
This is a very frequent pattern.
This mechanism is important to be aware of and can make all the difference in getting thyroid hormone dosage correct for the person.
Unfortunately, all too often what happens is that a thyroid patient has persuaded their doctor to allow them to add some extra T3. When they go back and say that it has not made any difference, the doctor just tells them that they did not expect it to, or that the T3 just does not suit them! Sometimes the T3 prescription is stopped and the trial is over! This happens a lot!
However, if adding some T3, results in a clear improvement that then disappears, one has to suspect the above mechanism is operating.
This is a big clue that the patient does need higher FT3! So, it should be seen as encouraging and not disheartening.
What can be done if this pattern of feeling better then worse again after a thyroid increase happens to you?
Excluding other common problems may be helpful. Running the full iron panel is a good idea. Having a cortisol saliva test and 8:00 am morning cortisol blood test is also sensible, as is testing other things that might be low like B12, folate, and vitamin D, etc. See my blog post on B12 though, please.
If the patient is on T4 medication (Levothyroxine/Synthroid) only, one approach is to continue to increase the T4. Eventually, TSH may get sufficiently low that an increase does provide extra T3. But this depends on how well the patient converts T4 to T3.
If T3 medication has been added, a good way forward is to slowly increase the T3 content of thyroid medication using 2-4 divided doses. This can frequently resolve the problems. Eventually, the addition of the T3 is sufficient to actually add and retain extra FT3. The T3 content may sometimes be T3 or NDT (depending on which is most appropriate).
It may also be very necessary to reduce the amount of T4 based medication that you are taking, whilst increasing the T3 medication. This can switch the balance to more T3, without having the same suppressive effect on TSH. By lowering the T4 medication, and having increased the T3 medication, this can avoid any increase in rT3 (and the presence of more D3 deiodinase enzymes that actually block the effectiveness of the T3).
Note, when TSH is very low, or fully suppressed, the mechanism described here ceases to operate (TSH cannot get lower) and further additions of T3 begin to actually add FT3. However, if T4 has not been lowered, it is still possible to have issues with rT3/D3 deiodinase enzymes when T3 is added, so the T4 medication might need to be reduced (sometimes a lot).
Sometimes, if the rT3 level of the patient remains very high (a marker of high D3 deiodinase enzyme levels), bigger reductions of T4 may be needed.
It is all about getting the right balance of T4 and T3 medication for the individual thyroid patient.
Importantly, research has now shown that a suppressed TSH when on thyroid treatment is acceptable. It does not mean the person is hyperthyroid or thyrotoxic. A suppressed TSH in a thyroid patient under treatment with thyroid medication is an entirely different situation to a patient who is not on thyroid medication. Unfortunately, many doctors and endocrinologists are still not making use of this research!
My latest book ‘The Thyroid Patient’s Manual’ covers both the mechanism described here and the research explaining that a suppressed TSH is safe when a patient is on thyroid medication (if there are no symptoms or signs of hyperthyroidism). I also wrote about this mechanism ten years ago when I wrote ‘Recovering with T3’.
2 + 2 does not always equal 4 with thyroid hormones
Adding some T4 or even T3 medication to your existing dosage may not always increase your FT3 level.
However, knowledge is power! In this case, it helps to set expectations, and helps patients and doctors to understand this response, if it occurs, and know what the next steps might be.
It can be a tricky balancing act, but knowing this at the outset should help greatly to get to a working dosage of thyroid medication that alleviates your symptoms – which is what we all want.
As ever, I hope this information may be of some help.
At the end of this blog post are some additional research references for those interested. I also wrote a blog post a long time ago on this same topic that I will reference here for completeness:
Additional research references:
Experiments have also been done with the livers and kidneys of rats that have been removed from their bodies. The livers and kidneys were kept alive and the experiments suggest that the addition of TSH can also affect conversion rate in these organs:
“Effect of thyrotropin on conversion of T4 to T3 in perfused rat liver”
Ikeda, Takeuchi, Ito, Murakami, Mokuda, Tominaga, Mashiba.
See: Life Sciences, Volume 38, Issue 20:1801-1806, 1986
“Effect of TSH on conversion of T4 to T3 in perfused rat kidney”
Ikeda, Honda, Murakami, Kuno, Mokuda, Tokumori, Tominaga, Mashiba.
See: Metabolism, Volume 34, Issue 11:1057-1060, 1985.
Note: in these last two experiments, T4 medication was added to the rats’ livers and kidneys. There was a control group of livers/kidneys in which no TSH was added and a group that had TSH added. Upon addition of extra TSH, the level of FT3 in the this group increased, suggesting that TSH was affecting the deiodinase up-regulation. Liver and kidney tissues are not supposed to have TSH receptors within them, so more research in this area is required.
Further research papers illustrating the way in which FT4 to FT3 conversion is not fixed but variable and regulated:
“Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment”
Hoermann, Midgley, Giacobino, Eckl, Wahl, Dietrich, Larisch.
See: Clin Endocrinol (Oxf) (2014) 81:907–915. doi:10.1111/cen.12527
“Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment”
Hoermann, Midgley, Larisch, Dietrich
“Relational Stability in the Expression of Normality, Variation, and Control of Thyroid Function”
Hoermann, Midgley, Larisch & Dietrich.
“Relational stability of thyroid hormones in euthyroid subjects and patients with autoimmune thyroid disease”
Hoermann, Midgley, Larisch, Dietrich.
Eur Thyroid J. 2016;5:171-179. doi:10.1159/000447967
“Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control”
Hoermann, Pekker, Midgley, Larisch, Dietrich.
Eur J Clin Invest. 2020;50 doi:10.1111/eci.13192
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