Hungry for Sherbet Lemons?

I've seen or heard many times viewpoints expressed that suggest that there are ideal levels of FT4 and FT3. I disagree with this.

A Recap of Basics
T3 is the most potent thyroid hormone. A single molecule of T3 active in the cell is ten times more potent at making the cell work than T4. T3 also binds more easily to the thyroid receptors in the cell nuceli. A thyroid receptor is a bit like a lock and the thyroid hormone is a bit like a key. There are multiple receptors in the cell nucleus of each cell and in the mitochondrion in each cell (which makes the energy needed for the cell).

Thyroid hormone is bound to protein mostly but some is 'free' which means it is unbound and able to pass through the cell membrane and into the cell. We feel well when enough FT3 has bound to the thyroid receptors.

FT3 operates genomically at the cell nucleus, which means that it has the effect of making some genes 'go to work' and begin their process of making proteins. The way it does this is through something called 'gene transcription' but that is beyond the scope of this blog post. Just think about it as the T3 affecting the cell nucleus in the most profound way it can, in order to make it metabolise/work faster.

FT4 does not operate genomically at all and its effect is much weaker on the cells - not 3-4 times weaker as sometimes is stated but 10 times weaker at least.  FT4 binds to receptors on the cell wall and can act non-genomically there. 

FT4 also enters the cells and can be converted within the cell to FT3 or rT3.

Reverse T3 (rT3 is an FT3 blocker) - i.e. it reduces the D2 deiodinase enzyme and thus lowers T4  to T3 conversion - lowering T3 levels in those people with any significant T4 in their body.  RT3 is converted from T4 by D3 deiodinase enzymes. High levels of D3 deiodinases are known to hinder T3 hormone binding to receptors in the cell nuclei. So, high rT3 can be a marker that T3 is blocked. 

RT3 is also necessary as it provides a means of clearing excess FT4 and for lowering metabolism when needed. RT3 slows metabolic rate. FT3, and to a far lesser extent FT4,  speed metabolic rate up.
RT3 is not a poison, and it is necessary for most people, but some people (a lot of Hashi's patients for instance) have very delicate (broken?) metabolisms and have a hard time coping with rT3 and in some cases FT4. RT3 cannot bind to the nuclear receptors but can bind to the receptors in the cell wall. High rT3 levels will also cause fewer D2 and D1 deiodinase enzymes to be produced - so less conversion from T4 to T3. It tends to block the T3 but not at the nucleus. If anything, as rT3 rises as a result of poorer conversion to T3 (it is a marker of this), the D2 and D1 conversion enzymes fall and the D3 enzyme rises (D3 actually does stop T3 from accessing the cell nuclei). Anyway, rT3 does have some negative effects and is a brake on metabolism but it is mostly just another marker to look at. The real blocker of T3 is the D3 deiodinases and they may well be high if rT3 is very high.

If the amount of rT3 is too high for the person - this will indicate slowing metabolism, as FT3 is trying to raise metabolic rate. If rT3 is excessively high then the person may simply not have enough useful FT3 effect at the cell nucleus, i.e. it might be blocked due to the D3 enzyme. Most likely though T3 levels will have fallen due to the effect on having lower D2 and D1 deiodinase enzymes. 

FT4 has to be converted to enough FT3 to be of any use. If it is converted to too much rT3, there will be less FT3 and that won't be good. 

However, there are no hard and fast rules over how high is considered too high for rT3. Neither is there a good or bad FT3/rT3 ratio. Good judgement has to be used, looking at patient response to treatment.

A healthy person will have normal intracellular behaviours of FT3, rT3 and FT4.

Someone who has lost thyroid tissue will have lost part of their ability to convert well from T4 to T3. If someone has one or both of the gene defects that affect T4 to T3 conversion (DIO1 or DIO2 gene defects), they will also potentially have worsened T4 to T3 conversion.

Other problems may also exist for the individual that makes their thyroid hormones a) less effective than they were when they were healthy, and b) that are also contributing to other issues within the cells.

We cannot measure the exact levels of all the thyroid hormones within the cells. A blood test is just a measure of what is in the bloodstream.
We cannot see the exact intracellular conversion rate and what level of FT3, rT3 amd FT4 exists within the cells.
We cannot see how well the hormones are transported into the cells, nor how well they bind to the receptors.
This most critical information is invisible to blood testing or any other form of testing other than dissection (personally I am not up for that measurement of my hormones!).

We know from patient experience that:
1) Some people just cannot get well with T4 therapy (Synthroid, Levothyroxine)
2) Some people cannot even get well with NDT or T4/T3 - but more do well with this than with T4 alone.
3) Some people need T3-Only and almost no rT3 and FT4 in order to recover. This is not just about getting a high enough FT3. It is about the eradication of the FT4 and all the rT3.

In my own case, if I add any T4 to my working T3 dosage, my symptoms begin to come back (even if I then increase the T3 dosage). I need a FT3 a few points over the top of the reference range to feel well. But I also need FT4 near zero and near zero rT3 and near zero TSH. I'm not in the least hyper. Generalisations about a good FT4 and FT3 level can be misleading at times - for some people.

Consequently, for a few people FT4 also seems to be a hindrance. Whether this is due to the FT4 itself or the rT3 it can create I do not know for sure. I suspect that in my case, I make more D3 enzyme that blocks T3 access to the cell nuclei when I add T4. I also think any rT3 hinders my own system.

For some it is better to shift the balance towards more FT3 and far less rT3 and less FT4.

Sweet Shop (Candy Shop) Analogy

The analogy I've used on forums is based in a shop selling sweets/candy for children. It isn't a perfect analogy - but it gets the point across.

This is just an analogy is is not trying to be perfectly accurate.

Imagine there are three groups of kids. The group you are in is really keen to buy some sherbet lemons in the sweet shop. The sherbet lemons represent successful binding with cell receptors.

A neighbouring but kind of friendly group also wants to buy some and the bully's from the next town have turned up and they want to buy some also.

The three groups are all there in the sweet shop. You have to have enough presence in the sweet shop with all of your mates in your group to have a chance of getting the attention of the 4 people serving behind the counter.

The bullies (if they turn up in numbers) will just elbow you and jostle you and your mates out of the way - these are like rT3. You hope you don't have too many of them there.

The neighbouring friendly group are OK but they have the ability to get in the way, and some might get converted into the bullies gang.

If you really need to get those sherbet lemons for all of your mates,  then you really don't want many of the neighbouring friendly kids turning up either as they can interfere and possibly even join the rival gang - they are like FT4.

Your group (the FT3 kids) really need to be dominating in numbers if you are really hungry for sweets and want to buy a lot.

The Takeaway

Healthy folks with perfectly thyroid hormone function can tolerate the normal levels of the other hormones. It is Ok to have some bullies (rT3), and a good number of neighbouring friendly kids (FT4) are fine (even if they convert to a few more bullies),  because the normal kids (FT3) aren't so desperate for sherbet lemons (getting and being active at the receptors in the cells).

The trick is working out what each thyroid patient is, and if the are a 'desperate for sherbet lemons kid' or not? :)

All thyroid patients  are different and these differences can be quite significant.

So, doctors and endocrinologists treating thyroid patients, need a full toolkit of all the different thyroid therapies in order to choose the right solution for the individual.

T4, NDT, T4/T3 and T3-Only all need to be available for use if required.

Note: for those patients trying to use the Circadian T3 Method (CT3M) optional part of my protocol, I do suggest that a T3-Only CT3M dose works best.

Best wishes,


(Updated in November 2019)