Interesting paper which shows that (in the dog) elevated TSH stimulates the deiodinase enzyme that converts rT3 into T2. This means that if someone for example takes so much excess T4 as to suppress TSH and thereby raise rT3 levels as a "drain" to remove the T4 excess, this inhibits the removal of rT3 and potentiates possible interference with T3 activity. Another reason to be cautious about T4 monotherapy if a patient to get sufficient FT3 has to take more because of poor T4-T3 conversion. It suggests that the way out of this dilemma is to add T3 to avoid the rT3 buildup from excess T4 and TSH suppression.
Endocrinology
1983
Thyrotropin-Mediated Induction of Thyroidal Iodothyronine Monodeiodinases in the Dog
SING-YUNG WU
Nuclear Medicine Service, Veterans Administration Medical Center, Long Beach, and University of California, Irvine, California 90822
Endocrinology Vol. 112, No. 2
, 417-422 (1983)
Written by
diogenes
Remembering
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Thank you so much Diogenes for posting this. The info you provide is much appreciated.
Thanks diogenes. I don't convert well and as of 3 days ago I actually stopped taking my 50 mcg daily Levo, and am now taking a low dose of T3 only. I was feeling so poorly on Levo that I decided to just go ahead, since I've always had top of range FT4 levels from before diagnosis and on all tests up till recently. Was worried about RT3 but read on Dr Westin Child's site that adding T3 can act to drain excess RT3.
Thanks for posting. This paper is quite old, published before there was an understanding of the three deiodinases :- D1 (T4 to T3 + rT3, rT3 to D2), D2 (T4 to T3, rT3 to T2) and D3 (T4 to rT3, T3 to T2).
D1 is expressed in the liver, kidneys and thyroid. D1 is upregulated by high T4 levels.
D2 is expressed in the pituitary, brain, heart, muscle and skin. D2 is upregulated by low thyroid hormone levels, most likely via TSH. There is no concrete proof that TSH stimulates D2 but I believe it does. As well as some complex papers suggesting TSH stimulates D2 the progress of hypothyroidism whereby TSH rises dramatically, fT4 falls and fT3 tends to remain stable (until the hypothyroidism is more severe) suggests TSH increases the rate of D2 activity.
Note that uniquely pituitary D2 is not regulated by thryoid hormone or TSH levels, it converts T4 to T3 at a steady rate. This makes sense the pituitary wants to measure the actual hormone levels, the peripheral tissues alter deiodinase activity in order to regulate cellular T3 levels.
D3 activity increases as fT3 levels rise.
So, if we have high fT4 and low TSH, D1 (T4 -> T3 + rT3) will predominate over D2 (T4 -> T3) resulting in higher rT3 levels. This is in addition to the effects of TSH on rT3 pointed out by Diogenes. rT3 binds to thyroid hormone receptors but is inactive, so higher rT3 levels blocks thyroid hormone activity.
Sorry if this is complicated. In short high fT4 produces more rT3 reducing hormone activity. Higher TSH produces more T3 and less rT3.
This is very important because many patients have a down-regulated hypothalamic pituitary thyroid axis - their 'set point' is lowered. This can happen if the patient has a sustained period of thyroxtoxicity (as far as the pituitary is concerned), either because of taking TSH suppressive doses of thyroid hormone or during the onset of Hashimoto's. In some cases they might not have been aware of being a little hyper before becoming hypothyroid.
The consequence of a lowered 'set point' is that their TSH is lower than it should be. So, if they receive levothyroxine their TSH will fall prematurely. More importantly they will have reduced D2, their fT3 levels will be lower than a similar patient with a normal 'set point'. If they are given more levothyroxine their TSH will fall even further and fT3 will also fall. Given even more levothyroxine these patients will have high fT4 and fT3 but most of the T3 will be derived from D1 rather than D2, with consequent high rT3 levels and refractory hypothyroidism.
If a patient has a lowered 'set point' they will require a higher proportion of exogenous T3 than a patient with a healthy set point. These patients will not respond well to levothryoxine.
TSH can be a very useful tool for diagnosing and treating primary hypothyroidism, but only if the patient has a healthy 'set point'. It makes sense to ask the question 'do the TSH, fT3 and fT4 figures look consistent?' before placing any reliance on TSH. I see a lot of symptomatic patients on these forums with low normal TSH, fT3, fT4 which suggests the condition is common.
TSH can be a very useful tool for diagnosing and treating primary hypothyroidism, but only if the patient has a healthy 'set point'.
Doing only a TSH test, without first demonstrating that the patient has a healthy 'set point', renders it both not useful and potentially dangerously misleading in those who have any but "within range" "one size fits all" levels. Back to shoehorning.
That's what I'm saying, you can't use the TSH until you know it is working correctly. Of course if you do a TSH screen and it comes out really high then you can respond to it, this is what happens for example when babies are tested a few days (?) after delivery, you cant' go by symptoms but you can avoid cretinism by using TSH.
Ultimately a person is hypothyroid if they have signs and symptoms of hypothyroidism which respond to thyroid hormone treatment. It it's primary hypothyroidism (only) then the TSH will be elevated (usually above 10.0) and TSH will be a good tool for helping to titrate medication. If the axis is faulty or there is resistance to thyroid hormone or endocrine disruption then TSH is less useful or of no value.
Sometimes TSH is great for diagnosis and treatment and sometimes it is no use, the trick is to decide when it is useful.
Yes. The TSH is useful for picking up primary hypothyroidism in neonates, it will not pick up central hypothyrodism or endocrine disruption. TSH has its uses. Other forms of hypothyroidism will only be picked up when signs are noticed, presumably months or years later. Fortunately these other forms appear to be rare (other than endocrine disruption which we have no test for).
'rT3 binds to thyroid hormone receptors but is inactive, so higher rT3 levels blocks thyroid hormone activity.'
jimh111, in a previous post, diogenes has said that we now know this not to be true. T3 and rT3 have separate receptors, and rT3 does not block the T3 receptors. Are you saying this isn't true?
No,I do not think rT3 and T3 compete for receptor binding: there is proof that both have their own noninterfering receptors. That does not mean that in the cell rT3 and T3 compete somehow for helping or hindering cell activity. But there no-one knows what is going on.
What we do know is that it is a symbol of disturbance in T4-T3 conversion either by nonthyroidal illness or overdosing on T4. Exactly what its effects are is not known; if there are any its not interference in receptor binding but interference in internal biochemistry of the cell.
I need to get more cynical about alternative physicians. Reverse T3 is inactive, some physicians state that rT3 competes with T3 for nuclear receptor binding which seems reasonable. I took this at face value and should have questioned this statement.
I can’t find any studies on rT3 binding to the thyroid hormone receptors (TRα1, TRα2, TRβ1, TRβ2). A general suggestion is that rT3 somehow stops T3 getting to the receptors. This seems reasonable as patients with high rT3 display hypothyroid like symptoms and rT3 increases in potentially thyrotoxic situations.
So, rT3 is inactive and there seems to be an unknown mechanism by which rT3 prevents T3 binding. Sorry for the confusion.
Isn't more likely that people with high rT3 display hypothyroid-like symptoms because they also have low T3? I've never seen anyone with high rT3 and top of the range T3 at the same time.
PS, I wasn't actually confused at all, just wanted to see what you would say.
You're right in respect that patients with non-thyroidal illness (NTI) tend to have high rT3 and low T3. I had in mind patients on large doses of levothyroxine who have high fT4, fT3 and rT3 but don't get better.
A couple of years ago I did an experiment. I stopped thyroid medication and measured my TSH, fT3, fT4 whilst on incremental doses of levothroxine: 0, 50, 100, 125 mcg.
From 0 to 100 mcg my fT4 increased steadily from 13 to 18.4 and my fT3 decreased from 4.3 to 3.6. The small dose increase from 100 to 125 mcg made my fT4 jump to 24 and fT3 to 5.5. I assume type-1 deiodinase took over from type-2 as my TSH dropped to 0.02 and fT4 was above the upper limit (22.0).
My symptoms improved as I went from 0 to 100 mcg but there was no benefit in the 125 mcg dose, even though the hormone levels were quite a bit higher. I assume it is due to rT3 production by type-1 deiodinase.
I do well on 100 mcg L-T4 plus 15 mcg L-T3. I was on high dose L-T3 for many years which I believe down-regulated my axis (my TSH on no medication was 2.64 with low normal fT3, fT4 and hypo symptoms. If the axis is underperforming just a little it leads to lower hormone levels AND impaired peripheral deiodinase which is not corrected by extra L-T4.
Diogenes, apologies I hadn't seen your post below regarding receptors when I made my earlier suggestion of competitive binding.
One point we overlook iis that D2 takes place close to the cell nucleus in the endoplasmic reticulum whereas D1 and D3 are located close to the cell membrane. This suggests the purpose of D1 and D3 is more to do with regulating plasma levels of T3. The big question is does the location of D2 affect T3 saturation levels at the receptor in the nucleus? i.e. do we have a higher density of T3 at the receptor than we see in the plasma, as a consequence of D2 activity? This is important because if D2 is reduced due to a down-regulated axis then restoring serum fT3 levels with exogenous hormone will not restore T3 levels in the nucleus of tissues that rely on D2. These patients will require higher serum fT3 levels than normal to resolve hypothyrodism in D2 expressing tissues, such as the brain. On the other hand tissues without D2 activity would be subject to too much T3.
I suspect many patients with autoimmune hypothroidism have a period of thyrotoxicity which down-regulates their axis. The only way to 100% correct their condition is to restore the axis set point or supply TSH treatment (not available) as well as L-T4 / L-T3.
All this shows the great complexity of the system and the multiple interlocking responses to potential change. I think our group has nearly got to a finale on elucidating the whole picture. A key piece of research we're planning is to find out the spread of the proportion of direct production of T3 by the thyroid, vis a vis body T4-T3 conversion, and tissue sensitivity to T3. We already know that in the healthy population, individuals can exist in a perfectly healthy state with FT3 levels a factor of two different from each other. This implies a significant difference in tissue sensitivity to T3 stimulation. The question is: how is this modulated by various combinations of direct thyroid T3 supply and body conversion and is there a relationship between these combinations and the steady state FT3 level needed by an individual. Secondly how are these combinations and sensitivities affected by thyroid loss and what bearing has this on suitable therapy? If we can get a handle on this I feel we are nearly there.
Yes that's the point. Whatever the potential interferences between T3 and rT3 (not on receptors but perhaps somewhere else in the cell biochemistry), if rT3 is low and T3 is OK, then there isn't much competition. I've read somewhere that rT3 is degraded to T2 by deiodinases 1 and 2, and T3 to T2 mainly by deiodinase 3, but I don't know for certain that's right. The big point is that there is a nice balance if you have the right treatment level, but as soon as you overdo T4, rT3 rises, TSH is suppressed and the whole works of rT3 degradation to T2 starts gumming up.
I have conversion difficulties and suppressed tsh at any dose of t4 or t3 that makes me feel remotely decent. For the sake of argument, let's say that my hpa axis is not functioning correctly when it comes to tsh. I have no thyroid tissue due to total thyroidectomy. I currently have a ft3/rt3 ration of 13. Would the exogenous administration of tsh aid in t4 to t3 conversion and rt3 degradation? I'm just thinking on a theoretical level and wondering if it has ever been approached from that angle. Current medical treatment for central hypothyroidism involves the supplementation of thyroid hormones, but that seems like an incomplete solution that disrupts a very sensitive system, because the range of tsh effects is overlooked.
Even if it was practically possible it wouldn't help much. TSH is a protein that is digested immediately you take it by mouth, and its lifetime by injection is too small and would need continuous infusion.
What relevance does this paper have, if any, to people (like me) who take T3 only? My levels of Free T4 are extremely low, so my Reverse T3 must be practically non-existent as well.
That should be true! The argument is attacking those GPs and others who think you can cure thyroid loss by cramming T4 into someone willynilly and expect somehow to succeed. This shows why it can't be done in cases of poor conversion.
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I don't convert well and as of 3 days ago I actually stopped taking my 50 mcg daily Levo, and am now taking a low dose of T3 only. I was feeling so poorly on Levo that I decided to just go ahead, since I've always had top of range FT4 levels from before diagnosis and on all tests up till recently. Was worried about RT3 but read on Dr Westin Child's site that adding T3 can act to drain excess RT3.
How long does reverse T3 last and why isn't it T3 that needs cutting not T4?
Hypothetical re: non conversion of t4 to t3 in hypothyroidism hashimoto's 
High Reverse T3
Reverse T3 dominance
A ramble concerning Reverse T3 ratio/ DIO2 polymorphism and dosing. 
