This is a study from 2013 that I missed. It is an ongoing struggle for science to understand the difference. So far, other than the DIO2 polymorphism, science is having a difficult time unraveling why we can react so differently to the various thyroid medications. PR
Conclusion
"Despite similar TSH levels, several peripheral tissues seem to register different T3 availability during T4/T3 combination substitution to hypothyroid subjects. Both hepatic function and collagen production during bone
formation seem to be stimulated. Our study, as well as other recent studies, encourages the development of
prolonged T3 formulations and testing in the clinical setting. However, the benefits of our findings are still
I've missed this one as well. The really important finding is that products involved with eg liver activity (sex hormone binding globulin) are stimulated by combination therapy. This supports what we've found in the upcoming paper and demonstrates the value of SHBG measurement as a marker for nonthyroidal tissue activity. The finding that T4 therapy can lag as a complete restoration of general tissue function is becoming more and more evident. Actually it could be that SHBG measurement would be a good co-diagnostic with the usual thyroid parameters.
Diogenes, it seems that it is becoming more evident that T4 monotherapy results in lower T3 tissue levels for many people beyond the DIO2 polymorphism problem. One paper I read said that they found lower levels of T3 in the CNS determined by measuring the cerebral spinal fluid, in people on T4 only. Glad I wasn't in that study. And yet there are people who seem to do just fine on T4. Are their bodies compensating by some means that we don't understand? Or are they just adapting to the situation. I fear we have a long way to go before science really has a thorough understanding of it all. PR
For what it's worth I think it depends on a) the degree of thyroid loss and b) how quickly one gets diagnosed and properly treated thus minimizing stress and longterm insult to the body. If you have a degree of residual thyroid action left I think T4 should work. The crossover point could be quite low for thyroid reserve no longer to be able to be adequately supplemented with T4 alone. I also have a theory that prolonged stress damages the T4-T3 conversion process irrevocably so that if a patient is not diagnosed early and suffers long term, then no amount of supplementation with T4 alone will suffice. The deiodinase enzymes/receptors simply are not active enough and T3 should be given as well. I think stress causes genetic changes which are not easily reversed. Additionally genetic polymorphism (different types) in deiodinase activity will play a part. If genetically you don't have particularly active deiodinase before the illness, this won't help to use T4 alone to cure the illness.
That's really interesting. I have the same opinion about the effects of long term chronic stress on the body. I was brought up in an abusive family and am absolutely convinced it has affected my body, in many ways. And it simply isn't considered by mainstream medicine. But living the whole of your childhood in abject terror is bound to leave its mark, I think anyway
HarryE, we were having a discussion about abuse and stress and the changes it caused a few weeks ago. Other than Diogenes, Dr. David Derry is the only one I've found that understood the correlation. This is a quote from an interview he did with Mary Shomon, "People who have had terrible childhood experiences (sexual abuse, physical abuse, personal tragedies etc) for whatever reason have altered thyroid metabolism. They are more complex to treat. They are different from everyone else biochemically and pharmacologically. The blame for most of their residual difficulties is not with their brains and minds but with their chemistry. I believe also other areas of their biochemistry are not normal. I don't think this has been generally recognized yet."
This is the link for the interview if you care to read it.
Yes, I've seen that interview, I cried a great deal when I read it! I've only just started on NDT so I don't know about my dose yet really. I'll have to think about other pharmaceuticals, not really sure, but I did have a really extreme reaction to high dose steroids!
I too had an abusive childhood and saw and heard stuff no child should go through ..I lived in a permanent state of fear ..I left home very early 17 but always shook or shivered when I was scared of something this continued till my 40s I always thought when I was diagnosed that possibly the stress of my childhood brought this on ..
You'll be happy to know that both of my collaborators Hoermann and Dietrich are very open to the stress/epigenetic idea. I n fact Johannes Dietrich told me he has encountered many people who have survived a hospitalized critical nonthyroidal illness but have never properly recovered their thyroidal health (and other health aspects too emanating from that). The realization of the phenomenon is more widespread than you think, but the explanation hasn't yet become accepted and so the tendency is to dismiss the problem as incurable..
Diogenes, your right, I am happy to know that there are doctors who understand the relationship. Hopefully they will talk about it with their colleagues and someday maybe someone will find it a desirable topic to explore. It has to be one of the major contributing factors in many endocrine problems and for many of us it makes getting adequate treatment next to impossible and usually costs us years of our lives. Unfortunately, that is also true for many with any kind of thyroid problem. If we keep banging on the door, sooner or later they will have to acknowledge that we exist. PR
As usual this site sets me thinking. What I propose is to ask my colleagues if they would think it possible and if so, help me in assembling a protocol for a GP to ask the right questions in the right order and the implications for diagnosis and treatment of the answers they get from the patient. My colleagues are doctors and I'm not, so I'd just take an editorial line in this if they agreed. It might help to use Thyroid UK as a disseminator of an agreed Q & A protocol so that the GP's could have a discussion base to work with. Again it might be too complicated ie patient-specific but it's worth asking them for their opinion on this.
Diogenes, I think that could be very useful. It is evident that doctors are not receiving adequate training in how to diagnose thyroid problems or in understanding the variety of thyroid conditions they will encounter. The training has to come from other doctors to be legitimate. Most doctors simply will not acknowledge any ideas that come from a patient. Please let me know what your colleagues think of the idea. PR
I agree, that would be a good start. I am finding out that there are some doctors that understand the concept but Diogenes is right, "the explanation hasn't yet become accepted." If we could get some accurate numbers on how many endocrine patients this affects I bet they would be significant. PR
It's a tricky one, there are all sorts of reasons why people would not disclose abuse, for example, even to a researcher. Medical or injury type stress might be easier. It is so true that the more we discover, the more we realise there is is still to discover. Unless of course you are an endo, in which case you know it all already
I agree with both diogenes and you HarryE and both of you are both describing my situation exactly.
Wasn't treated early enough, prolonged stressors, high antibodies and debilitating symptoms for at least 18 months before I was treated (also head injury as a child and mild hypo symptoms since - I also think I have a degree of secondary hypo that has muddied the water as I am TPO positive).
I have tried T4 alone which made me worse and I was on that for over 3 years unable to get out of bed / leave the house. T3/T4 was better, but not enough to recover my health. Now I take t3 alone and I am much better, but quite unstable. Its not ideal...and the body is significantly deconditioned due to this going on for 8 years or so...
Just got a new GP (3rd time lucky) who is ordering an USS of my neck and is taking me seriously. He is speaking to his friends to find me the right endo referral (I have seen 2 already who just say I have CFS).
I also have some NDT on standby, but GP has asked me to wait until the latest tests are done and he finds the right expert to help me. Only seen 8 doctors before him but better later than not at all...I will now see what happens next...fingers crossed...
Diogenes, in regards to stress, that is exactly what we were talking about before in children who have suffered abuse or a great terror or fright or bullying. It is the extreme stress of the situation that causes the changes. That is what Dr. Derry believed, that is changed the biochemistry. One thing Dr. Derry told me was that NDT seemed to work better in this class of patient. As I said it is the perfect example of epigenetics and is largely unrecognized and has not been studied. What we do not have is a clear idea of how it changes the biochemistry. I also agree about the 'how long' factor and to that I would add 'how adequately treated'. As Drs. Derry and O'Reilly noted the average normal dose pre TSH test was two to three times the average normal dose post TSH test. There have been numerous examples on the forum of people who once they got on adequate replacement were able to stop many of their other prescriptions. They were given other prescriptions because their doctors never gave them enough, or the right kind (T4/T3), of a replacement dose. The old adage of giving a patient enough thyroid until their symptoms disappear and the patient feels well is actually pretty correct, but far too often ignored. That is the other aspect of thyroid, it is the persons' sense of 'well being'. I don't suppose we could get you to train some doctors and get them on the right track. PR
Well, you could have fooled me and many others here at the forum. We find you eminently qualified. Goodness knows I'm sure I could have never made it thru an advanced degree in 'physical' chemistry, not even on my best day. PR
PS I had to have a close relative who has a minor in chemistry explain to me just exactly what 'physical chemistry' is.
I appear to fit your profile for someone who has recovered well on T4 monotherapy. I also have low autoimmune antibodies, so it's less likely that my hypo is autoimmune - I think this could also be relevant. It has still taken me two years to learn to manage the condition and build up my muscle strength...
Your comment here is exactly the same direction as I have been thinking.
I am also starting to question the whole protocol of starting low on t4 and slowly incrementing, only switching to T3 if, possibly after years of trying, T4 alone does not resolve the problems.
Is there a possibility that some seriously different protocol might work better? For example, treat on T3 only until the patient is well, with a fairly fast rate of increase. Then try to changing over to T4, slowly replacing a little T3 by T4. Eventually either T4-only or some balance of T4 and T3 should be found that works for that person. All that without subjecting them to long periods of inadequate and/or ineffective treatment thus keeping them hypothyroid.
There was a member here who said her doc put her on an increasing level of t3 until she felt she could tolerate no more (possibly she then took slightly less than her 'maximum' dose), then added t4. I would give a more detailed description if I could remember it a bit better.
I had never heard of anyone being treated this way.
I lost track of this person here and have been looking for them to learn more about this method of treatment but so far have not been successful. They said that they remembered this process of getting well as well as the day their child was born.
I even did a post asking them to contact me but no luck, and I looked back through 'my activity' but I concluded that the thread had been deleted. healthunlocked.com/thyroidu...
I wonder if they'd been treated abroad because I'd never heard of a doc here taking such a free hand with meds. Docs everywhere do not fear overmedication more than they fear undermedication; for some, possible short-term hyper symptoms are just part of the process of finding the right levels to restore wellness.
Rod, I think you have touched on a fascinating and very difficult, multi-faceted problem. The Drs. (MD PhD) Shames made an interesting observation in one of their books. They said that after 30 years of treating thyroid patients they still had not been able to determine any pre-indication of which thyroid medication would work best in a patient. You had to try one and then look for results, if you didn't get the results you wanted then switch medications. This is one of the key problems thyroid patients face, doctors only look for results in the blood test and not in the patient, and many refuse to give the patient any options. Better education for the doctors is the only solution for that and perhaps more use of the DIO2 test.
If you look at the various studies of T4 monotherapy versus other choices, even though a lot of them are all over the place, there does seem to be a definite preference for T4/T3 over T4 only. In Dr. Wiersinga's latest paper from January, Table 3 shows the cumulative results from 6 random, double blind, crossover studies, 48% preferred T4/T3, 27% no preference and 25% preferred T4 monotherapy. These results parallel the Danish and Walter Reed study. The preference for T4 is definitely the minority position. Given that 75% either prefer T4/T3 or have no preference you would think that combo therapy would be the first choice of doctors, if they actually practiced EBM. Doing that would of course give people some T3 right from the start.
What I'm curious about is why did 25% prefer T4 only, why did it work better in their biochemistry? Diogenes could very well be correct in his analysis of why. Dr. Derry noted that the longer it took the harder it was to get people back. Then you have those who only achieve success with T3. There the only hint I can think of is bi-polar or depression and not all on T3 had either of those problems. Again we come back to the doctor paying attention to the patient and willing to try various options.
Then there is the question of what dose do you start at and how quickly do you raise it. Like most things in the thyroid world there seem to be multiple options used with varying results. You and I have both read posts from people who raised it too fast and had to back down and start over because they didn't give their bodies enough time to adjust to the change. And again you need a doctor who is actually paying attention to the patient instead of the blood test.
For me it always comes back to changing the way doctors practice medicine and that is a monster to tackle. Here in the US medicine is incentivized for profit, 'health' and 'care' seem to be farther down the list. Many of the 'good' doctors have to operate on a cash basis to survive, insurance won't pay for most of what they do. This is similar I think to the UK and people going to see 'private' doctors. If you come up with the answer please let me know. I seem to struggle with how to make effective change happen. PR
The main problem as I've been told it is that rushing things too fast after a period of hypothyroidism can cause an over-reaction and temporary disabling hyper symptoms and fluctuations. The buildup of therapy whatever it is has to be gradual to avoid this, because often the basic health of the hypo subject can't take the extra load immediately. I think T3 would be too severe a starting point because of its potency and short life. Unhappily the hypo person has to endure some "buildup" time, but of course this should be done efficiently at the best possible rate and when some kind of balance has been achieved, then one can look at T4-only, T4/T3 or T3 depending on how that balance presents itself (i.e very good, merely satisfactory or leaving much to be desired regarding patient QoL perception). It's called intelligent diagnosis and treatment involving the patient as chief diagnostic. I can't see a "symptom-free" resolving period as a practical reality.
I was pretty healthy until this thyroid issue began. I first went to the docs at Xmas about the lump in my throat, although looking back this had probably been coming on for about six months. Even so, I have been very careful to build up slowly, frustrating though it is now I am starting to feel a bit better. I chose NDT simply because , as I was going to have to pay for whatever I used, I decided to go for what I had heard most good feedback about. I may respond well to Levo, but I just don't know. But I can imagine that if I had been ill for a much longer period, it would have been a huge shock to my system. I am very grateful I found so much help and advice so quickly.
Diogenes, if you can get "intelligent diagnosis and treatment involving the patient as chief diagnostic" accepted as the standard of treatment in allopathic medicine then all of us in the thyroid patient community, past, present and future, would owe you a debt of gratitude we would never be able to repay.
Diogenes, I like to ask you a question. When I started reading about thyroid some 25+ years ago it seemed generally accepted that the thyroid output was 80% T4 and 20% T3. ( and maybe some RT3 and thyronamines and who knows what else) In the last few years I've seen numbers like 90% T4, 10% T3, even 93% T4 and 7% T3. I asked an acquaintance who has a background in biochemistry and molecular biology and he said that 80/20 was correct. He said it has to do with the raw materials the body makes, T1 + T2, and the ratio in how they are combined to form T4 + T3. I'm sure he simplified the answer for me but is that reasonably accurate?
In the last 20 years with the various studies on T4 monotherapy versus T4/T3 therapy there has been a lot of discussion about the proper ratio of T4 to T3 to use. NDT is 4.22:1 and has worked exceedingly well for almost 120 years. (Although I will grant you that it has only been since the early 1980s and chromatography that we know for sure the ratio is 4.22:1) Many seem to think that that ratio is too high. I see comments in the studies that the proper ratio should be 10:1, 12:1, 15:1 or even 20:1, based on measurements in the blood, I believe. If the thyroid outputs 80/20 wouldn't the ratio in the serum be roughly the same? What are they basing the lower ratios on? I must be missing something in the discussion about all this. I don't clearly understand the basis for the various ratios. Appreciate any thoughts you might have. PR
The body does not make T4 (or T3) from T2 and T1 but from DIT and MIT.
Iodide is actively absorbed from the bloodstream by a process called iodide trapping. In this process, sodium is cotransported with iodide from the basolateral side of the membrane into the cell and then concentrated in the thyroid follicles to about thirty times its concentration in the blood. Via a reaction with the enzyme thyroperoxidase, iodine is bound to tyrosine residues in the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one particle of DIT produces triiodothyronine.
I am convinced that at least some of the claims that desiccated thyroid contains T2 and T1 is based on the confusion of MIT with T1, DIT with T2. (At least, amounts of T2 and T1 above the sort of infinitesimal trace levels that might be identified anywhere else in the body.)
Of course, it could easily be me that has it all upside-down and back-to-front with the rest of the world being right!
Anyway, your question about the T4:T3 ratio is nevertheless interesting. I also ask, what mechanism controls that ratio? (Or should that be, what mechanism controls the DIT:MIT ratio?)
Rod, this is the explanation I got when I originally asked an acquaintance about what determines the ratio.
"Hi PR,
Thyroglobulin contains the mono- and di-iodotyrosines that go to make up both T4 and T3 with the peroxidation reaction that joins them up....
It's the relative proportion of the two that determines the thyroid's output ratio of T4 to T3. There is proportionately less mono-iodotyrosine in the thyroglobulin than there is di-iodotyrosine based upon the greater likelihood that, ultimately, two iodine atoms will react with tyrosine than will one iodine atom.....in other words, once the tyrosine is mono-iodinated it can then be di-iodinated, but it doesn't complete all of those reactions.
It's to do with the reaction rates, forwards > and < backwards, for the latter reaction
2 x Mono-iodotyrosine + 'Iodine' as I2 < = > 2 x Di-iodotyrosine
.... that determines the so-say 'equilibrium constant' for the reaction.
If the temperature is changed or the proportion of reactants changes for any reason, then the overall 'position' (ie completeness) of the final reaction can change.
At 'Normal' body temperature, iodine content, and all things being equal, (so-to-speak) there is a 'predictable' outcome .... my language is a bit less precise than it could be, for the sake of understanding ...."
The T4/T3 ratio produced by the thyroid gland in health is about 80/20. Now for some calculations. The average total T4 for a truly average euthyroid person is 100 nmol/L about. The corresponding average FT4 produced from this is about 15-20 pmol/L (this is 2/100 of 1% of the total T4). The average total T3 is about 1.5-2 nmol/L (that is 1/50 of the total T4 ). The corresponding average FT3 is about 5 pmol/L (one third to one quarter the concentration of the FT4). This comes about because T3 is only bound on to the transport proteins at about 10% of the strength of T4. In this case FT3 represents 2/10 of 1% of the total T3. Thus 1 unit of total T4 would give 1/10 the amount of FT4 compared with 1 unit of T3 giving FT3. The true total T4/Total T3 ratio in the average person is about 100/2 = 50/1 whereas the FT4/FT3 ratio is only about 4 or 5/1 because of the weaker binding of T3. So it is true that ideally the T4/T3 ratio in NDT should be nearer 50/1 than 4/1. You have to distinguish between the fact that your T4/T3 dose goes straight on to the transport proteins, whereas the FT4/3 is determined then by the strengths of binding. I'd settle for 20/1 as a compromise. All this means is that I'd ideally supplement NDT with T4 to get that ratio.
Diogenes, thank you, that is the clearest explanation I have gotten and I think I understand it reasonably well. It does bring up another question but that will have to wait. It is tax time here in the US and I have to go finish some paperwork. They tend to get upset if you are late and charge you yet more money. Thanks again, PR
Diogenes, I have come to a dead end. The obvious question to me is if the thyroid produces T4/T3 in an approximate 80/20%, or 4 to 1, ratio, then why do all the estimates of the daily production of a normal euthyroid individual not show that. Apparently I am missing something very obvious.
and a couple of lessor PDFs on Endocrinology from educational institutions that I found on the web.
The estimates of daily production vary from your 100ug T4 and 1.5-2.0 ug T3 to 94-110 ug T4 and 10-22 ug T3
(Thyroid Manager but a 1971 reference) to 100 ug T4 and 10ug T3 or 90ug T4 and 10ug T3 (depending on which part of the text you choose at Endocrinology: An Integrated Approach) or 90ug T4 and 10ug T3 from one of the PDFs. There is no exact consensus but they are all in the same ballpark which isn't even close to a 4:1 output ratio. So if the thyroid produces T4/T3 at a 4:1 ratio why don't any of the estimates of daily production show that? What am I missing? Is there a control mechanism I haven't read about? PR
The consensus nowadays is for the 80/20 mix. But unfortunately your calculations are dealing in old money ie gravimetric weight which Americans are regrettably fixed on in contrast to the rest of the world which deals in molar (SI) units. In old money, allowing for the different molecular weights of T4 and T3, the ratio becomes 84/16 about. This is getting on to 5/1 in those terms. I think the other values have been superceded because I don't know of any European study with much bigger differences from molar 80/20. Additionally, Johannes Dietrich's computer simulation of thyroid activity uses a 80/20 figure as a benchmark.
Actually when you consider the implications it really doesn't matter too much if the thyroid excretion of T4 and T3 is 10/1 or 5/1. Either way, the thyroidal direct T3 contribution is very small compared with the T3 produced extrathyroidally from T4. And we've got to distinguish production rates from reservoir content. The first is a dynamic and the second is a virtual stasis with a very small dynamic "bleed" into the extrathyroidal tissues. Metaphorically the first can be thought of like a simple waterfall and the second is like an almost still pool with small falls into and out of it.
I view the HPT axis as the 'course tuning', its job is to keep the supply lines stocked. 'Fine tuning' takes place at the cellular level with the deiodinases and apparently the co-activators and co-repressors also play a part. That is to say that 'all control of thyroid is local, in the tissues and organs throughout the human body'. I struggle with understanding the finer details, also some of the major details, because of the obvious lack of training and education. There is no shortcut, you have to do the work.
Science still struggles with understanding why NDT seems to work so well for so many of us. The various studies so far have not really shed much light on this, other than if given the choice about half prefer combo therapy. It seems that many of us need the T3 that is supplied in NDT and that we do not experience any symptoms of excessive T3 in our bodies, we just feel normal. We are starting to get some clues, the DIO2 polymorphism and so forth, but our understanding is still limited. I also think that the longer it takes to get diagnosed and adequately treated, the more damage that can occur which we don't fully understand yet.
I appreciate your taking the time to help those of us struggling to gain a better understanding. We rarely get access to your level of training and knowledge. Those of us that have needlessly lost years of our lives
do not suffer from a lack of desire to understand. PR
Thanks Rod, it was the 1 and 2 rings that wasn't sinking in because of my lack of a good chemistry background. The person writing at the 2nd link is another that takes NDT with some T4. PR
There is no struggle, doctors are aware that T3 and NDT protocols work better with (most) people but are reluctant to look at the evidence because the big pharmacies won't allow it!!
Totally agree with the first bit - I'm also puzzled as to why it is so difficult to understand. Disagree with the last bit - I have become very well on thyroxine - I'm back to skipping 45 minutes each time 4 times per week - which was my routine before becoming hypo... so good health is possible. I think the tragedy is that everyone should be expected to achieve this on thyroxine monotherapy and the NHS are so restrictive in their approach. Anyone who remains below par should be tested more fully and offered another treatment. Simples.
Why is it impossible for some people to accept that there are many people who are actually well on T4. We are not resigned to feeling below par, we actually feel well. I would suggest that rather than being totally anti T4 and implying that we who are well on it are just living a lie that you be more open minded and accept that we don't all fit into your box.
As usual this message has appeared in the wrong place it was a reply to reallyfedup and others who are anti T4.
rfu. The point is i accept that some don't do well on T4 , my husband is one, he takes T4 and T3 and is doing better. I accept that we need medication that suits us, what suits one doesn't necessarily suit another. I would never imply that others who do well on a different med were blinkered and in denial. I have no working thyroid and am not on a high dose yet i am well. I just wonder why this is difficult to understand.
Yes, one of the charities I have been involved with has some research on the damage to the HPA axis. I'll try and find it to post. Although from all my reading on here and elsewhere, I think my adrenals are not too bad.
I now have adrenal problems and doctor admits a lot going on and he doesn't know what's wrong...t4 just been increased but if this doesn't work il try ndt ..I'm one of those not easily treated on t4
Was doing fine on Eltroxin, but now not good on current 3 Levothyroxine remedies. Just wish NHS would pay for decent medication and not spoil the ship for a ha'porth of tar. Janet.
Well rfu both my sisters and a cousin are all very well on T4 so that is 4 of us in one family, my late Mum was also well on T4 and had been for years. One of my sisters had a TT over 40 years ago and she has never had any problems whatsoever on T4.
You have your negative experiences of T4 which I understand but please don't assume that the rest of us who get on perfectly well with T4 are merely putting up with inferior treatment and are to brainwashed or brain dead to do anything about it.
Your words were " patients have simply resigned themselves to feeling below par and have forgotten what good health feels like" which is simple not true.
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PR 
T4/T3 Combination 
Levo / Lio Combination Studies - New Document
t3 only or combination t3/t4
