We were having a discussion of this matter just recently and I thought I had achieved an understanding. Then I came across this. Rod, Diogenes, any comments would be appreciated. PR
Mechanistic background
The thyroid gland secretes a variety of iodinated and non-iodinated molecules that collectively play important roles during prenatal and adult lives. Understanding what these molecules are and what they do informs our understanding of the therapy for hypothyroidism. The main non-iodinated molecule secreted by the thyroid is calcitonin, an endogenous hormone with probable effects on calcium and bone metabolism. The other iodine-containing molecules include T4, T3, reverse T3, 3,3’-diiodothyronine (3,3’-T2), 3,5-diiodothyronine (3,5-T2), monoiodothyronine (T1), and their decarboxylated forms known as thyronamines.
While the traditional view has been that T3 is important as the main iodothyronine with significant binding to nuclear TRs at physiological concentrations, and T4 is important as a precursor of T3 (458), the use of desiccated thyroid extracts for therapy of hypothyroidism is based on the hypothesis that other molecules present in the thyroid gland may have important effects. A growing number of in vitro studies have indicated that administration of pharmacologic doses of 3,5-T2 has metabolic effects, possibly mediated via non-genomic mechanisms, (459-461). Note that the mechanism by which 3,5-T2 is generated in humans is unclear; furthermore the circulating levels of 3,5-T2 is two orders of magnitude lower than T3 (462, 463). Finally, thyronamines have been shown to interact with the G-protein coupled receptor Transcript Antisense to Ribosomal RNA (TAR1), with 3-iodothyronamine being the most potent agonist. In pharmacologic doses 3-iodothyronamine triggers diverse effects such as hypothermia, behavioral inactivity, bradycardia, and decreased cardiac output. Metabolic effects such as a shift from carbohydrate to fat metabolism and stimulation of food intake have also been described (464).
In summary, current evidence supports the classical view that T3 and T4 are the only biologically important secreted products of the thyroid; none of the alternate signaling molecules have been definitely shown to have physiologic relevance in humans at endogenous concentrations. It is not known whether oral use of thyroid extracts would provide any of these “alternate” components to patients, since studies of their retention during product preparation, their absorption into the blood from the gastrointestinal tract, and subsequent concentrations achieved have not been published. The available literature does suggest that pharmacologic administration of 3,5-T2 and iodothyronamines could have metabolic effects.
The idea that there are additional hormonal entities related to but other than T4 and T3 involved in thyroidal control of metabolism has been long held but little researched. There are about 28 possible candidates to consider and only three or four have been looked at in any detail. One question is where these other substances come from: are they produced uniquely by the thyroid gland de novo, or do they come later in the tissues from the T4 and T3 already produced by the gland. The first group, if they exist, wouldn't be available to those with no thyroid activity but the second group would because of post (external dosage) T4/3 alterations. Examples of the second group are the sulphates and glucuronides of T3 and T4, reverse T3, Triac and Tetrac. The argument against the others having much of an impact lies simply in their tiny amounts compared with the T4 and T3 mainstays. To have a significant effect the minor components would have to have very large activity commensurate with their amount. This I find an important reason to doubt their effectiveness.
I take Erfa thyroid after a total thyroidectomy. I tend to believe that if something is in our bodies then it has a purpose, however small, which we do not yet understand. Since pig thyroid contains all the components of the human thyroid, although in different proportions, would that not suggest that T1,2 etc may be produced from the gland itself. Obviously that does not discount deiodinisation in the tissues. I hope I am getting all the elements from Erfa thyroid to replace my thyroid function, otherwise I'll feel I'm missing something!!
Here is a reference indicating that T2 at least is largely made extrathyroidally from T3 and reverse T3.
J Clin Invest. 1978 May;61(5):1276-85.
3,3'-Diiodothyronine production, a major pathway of peripheral iodothyronine metabolism in man.
Gavin LA, Hammond ME, Castle JN, Cavalieri RR.
This indicates that any T2 in NDT is small beer compared with what the body makes from T3 and rT3 outside the thyroid gland itself. T2 is an active hormone in special ways. T1 may be but not proven at all. in the thyroid gland, T3 is made directly from monoiodotyrosine and diiodotyrosine linking together to form T3. T4 is made by linking two molecules of diiodotyrosine together. Thus thyroidal T2 cannot come from these mechanisms except by losing an iodine atom from t3 after it has been made.
Glad to see you make the point that T2 is made from both T3 and rT3. I take that to further reduce the likelihood of thyroid-produced T2 being of significance.
On the calcitonin front, I believe there are differences between porcine and human versions. Do you know anything about this?
I think that looking at the rather sparse literature, that pig calcitonin extract is likely to contain relatively less than half the human equivalent. I have to modify this in the light of calcitonin assays being rather nonequivalent and inconsistent. but the overall picture does indicate much lower pig levels of CT.
It is necessary in the body to modulate the effects of T3 so that they are at a suitable level for your present state of health. For example, if you are suffering from a significant nonthyroidal disease then the body T4-T3 conversion alters towards more of a T4-reverse T3 change. This "damps down" the T3-mediated metabolism so that your body and tissues aren't working too hard using up calories and this allows you to recover from the disease better. A kind of semi-hibernation mechanism - like sick animals going into a corner to slow activity to help recovery. But you don't need rT3 from supplements - the body will do everything you need in T4 conversion.
I see, thank you for explaining.. I'm just wondering what happens for those taking mainly T3 - is there a need to reduce ingested T3 during non- thyroid illness? Will ingested T4 be converted to RT3 at a greater rate in the context of illness and a medication regime consisting mainly of T3? And isn't it the case that rT3 is bad news - doesn't it block receptors and so contribute to hypo symptoms?
rT3 is a defence mechanism that continually controls what your T3 is doing. The same amount of T3 if you are taking T3 alone might need to be modified a little if you become very nonthyroidally ill, because T3-rT3 conversion doesn't readily happen. With T4 dosing, of course, the balance of conversion to either T3 or rT3 responds to your overall state of health. rT3 usually doesn't affect things and inhibit T3 activity until it is necessary to do so; that is, its blocking mechanism is an attempt to stop T3-related metabolism going too fast for the circumstances.
So in a sense the potential for T4 to be converted to rT3 provides another route to natural adjustment of thyroid hormone level for someone taking T3/T4 combo in the context of continuously suppressed TSH?
So we need to hope for good tissue mechanisms to remove iodine atoms for T2 and T1 to be formed! It sounds as though research into the functions of all the other possible entities could prove interesting in the future. Thank you for the information.
So as a thyroidectomy patient, if I didn't have porcine thyroid I would not have even the low dose of calcitonin found in NDT. Is that not something I, and other thyroidectomy patients, need?
The research literature is sparse and rather outdated in looking at the content and function of the hormonal elements of human thyroid glands, should this be a possible source of research projects?
Diogenes, if you can't make a T2 out of two MITS is it possible some might be made by deiodination? And I realize we are talking small amounts and that almost all is made in the extra-thyroidal tissue. The two thyroid physiology textbooks I have access to online suggest part of the T3 in the thyroid gland comes from deiodination in the gland of T4. Is it possible there is also some D3 in the gland besides D2 and that it might make some T2 from either T3 or RT3?
I see I forgot to mention where this came from. deiodinase.org/ Dr. Bianco is one of the leading researchers on the deiodinases. He used to have most of his journal articles available on the site but I think he got in trouble and now has several presentations that he has given. deiodinase.org/2013/11/10/a...
I've been working my way through some of his recent ones like, "Defending Serum T3 is a Biological Priority". I actually recognize several of the names of the group that wrote the draft guidelines. Unfortunately, even though the Guidelines are full of references they don't list any for the 'Mechanistic Background'. Also unfortunately, not much new although they do mention the European guidelines about T3 as experimental but don't agree, of course.
On another note there seems to be some more silliness going on with NDT here in the US.
This seems to parallel some of the recent comments on here about changing rules for ordering NDT online.
Dr. Pepper mentions a study he and his colleague conducted which showed 80% preferred Armour to T4. They can't get the study published, no surprise. PR
Yes in the thyroid T4-T3 conversion is also a method of T3 production as well as the MIT-DIT interactions. I wouldn't be surprised if some T2 was made in the thyroid but if it is, the amount is very small indeed, and I think too little to have anything but a very local effect if at all. Bianco's a good worker - but he is involved in detailed biochemistry not really in diagnosis at the front line. And those two groups don't talk to each other or really understand each other.
I also think there is no evidence comparing the longterm outcomes of health and adverse events and mortality between T4 therapy and NDT. Mind you, this could only be done by measuring FT3 as a key guide. And FT3 is not flavour of the month in thyroidology.
This is a bit off subject but I have been looking at research investigating the effects of calcitonin reduction after thyroidectomy. This following Diogenes' interesting point about the low levels of calcitonin in porcine thyroid compared to human. It seems that a reduction in bone mass after thyroidectomy has been significant in male patients. Is this an indicator that NDT should be offered to patients after thyroidectomy so that at least some calcitonin is available to them? What happens to those patients who take thyroxine only when their bone mass is compared to those on NDT? Does anyone know of such a study?
A recent paper on oral calcitonin - not very encouraging. It seems that oral uptake of CT itself is not very good and a derivative has to be made to make it bioavailable. So pig NDT CT by itself may not be efficiently used.
The Oracal trial J Bone Mineral Res. Aug 2012 gives more hope and suggests oral calcitonin as a possible treatment for osteoporosis. I'm hoping the pig calcitonin is usable even if not enough!
Jeffrey Dach's site is quite comprehensive with lots of references, but he points out that bone strength etc and therapy has been confined to T4 therapy only:
The problem is that unless NDT is at least accepted as a treatment for a subset of patients, comparative longterm trials versus T4 only have no attraction (or funding) for investigators
Diogenes, I hope that they are not able to kill NDT. For those of us who don't get along well with T4 it would only hasten our departure from the planet. I think I found a doc who is using T3 in the ratios you suggest with good success. I've ordered his book so I can take a closer look. To me it is a continuum, some do fine on T4 only, some need some T3 (apparently with varying ratios) and some need T3 only, like Paul Robinson and Dr. Lowe. I hope we don't lose any options, we seem to need them all. PR
PS Dr. Dach's latest newsletter is talking about cannabis oil and it's therapeutic effects. Seems to be some real potential there.
Oh dear, I think that may have blown my argument that NDT has to be the treatment of choice for patients having a total thyroidectomy. I hold on to the belief that all thyroid hormone elements have a purpose which we don't yet fully understand. However in this case, if these elements, such as calcitonin, cannot be easily assimilated orally then how can thyroidectomy patients ever regain full health, whatever treatment they recieve?
It seems very sad that NDT, which was the only treatment for hypothyroidism until the introduction of synthetic thyroxine, should not still have acceptance for those patients who it may benefit and, therefore, attract research funding. So many people who suffer from thyroid disease are unsatisfied with their health after treatment.
I was blessed to have a concerned GP friend who advised NDT after my thyroidectomy when viewing the zombie I had become. Dr Skinner supported me then with my own GP surgery. I hope that I will be left on my present medication now he has gone. I am concerned that the loss of this small but essential gland, in whatever way that occurs, predisposes patients to other diseases which then require other interventions, all with side effects.
None of the research seems to point to a better future for people like me!
Desiccated thyroid may well be the best available treatment for some people. However there are quite a number of people who find that they do best when combining that with levothyroxine and/or liothyronine.
Even if it is the best, there seems little reason to think that the proportions of whatever is in desiccated thyroid are optimum for everyone. We simply do not know how much of everything is in the original porcine thyroids, let alone how much remains in the tablets at the end of the production line, nor how much will be absorbed. We are a long way from knowing, and even further away from being able to reliably control these quantities.
Rod, with the exception of T4 and T3 which are assayed for standard amount, but yes, everything else seems to be a question mark. Personally because of antidotal experience in the family I believe there is something else which also has an effect, have no idea what it is. PR
One of the big problems with the unknown factor X is knowing whether or not it is present. Maybe it varies between products? Maybe it has been affected by the various changes (intentional or simply due to the variability of ingredients) over the years? Maybe it is affected by the whole tablet production process as it currently exists?
The history of B12 shows us something of this - maybe someone, somewhere will eventually identify the special factor which makes the difference?
Although there is a rooted anti-synthetic thyroid hormone view, perhaps, with understanding of things, some sort of neutral ground might eventually be found? Even if all it does is provide the understanding and a means of reliably assaying desiccated thyroid products. After all, few people go out of their way to avoid factory produced B12 and consume only vast quantities of liver.
B12 deficiency is the cause of pernicious anemia, an anemic disease that was usually fatal and had unknown etiology when it was first described in medicine. The cure, and B12, were discovered by accident. George Whipple had been doing experiments in which he induced anemia in dogs by bleeding them, and then fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. In the process, he discovered that ingesting large amounts of liver seemed to most rapidly cure the anemia of blood loss. Thus, he hypothesized that liver ingestion might treat pernicious anemia. He tried this and reported some signs of success in 1920.
After a series of careful clinical studies, George Richards Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. They also found that an entirely different liver substance cured pernicious anemia in humans, that had no effect on dogs under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. Minot and Murphy reported these experiments in 1926. This was the first real progress with this disease. Despite this discovery, for several years patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice.
In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine.
These events in turn eventually led to discovery of the soluble vitamin, called vitamin B12, in the liver juice. In 1947, while working for the Poultry Science Department at the University of Maryland, Mary Shaw Shorb (in a collaborative project with Folkers and Merck) was provided with a $400 grant to develop the so-called "LLD assay" for B12. LLD stood for Lactobacilis lactis Dorner, a strain of bacterium which required "LLD factor" for growth, which was eventually identified as B12. Shorb and colleagues used the LLD assay to rapidly extract the anti-pernicious anemia factor from liver extracts, and pure B12 was isolated in this way by 1948, with the contributions of chemists Shorb,[66] Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. For this discovery, in 1949 Mary Shorb and Karl Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences.[66]
The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data.[67] Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease.
Rod, I would settle for someone just doing a thorough analysis with the best modern methods available to see just what exactly is in NDT. And we both know that is highly unlikely. The effect has been consistent over thirty years and has to do with the freshness of the NDT. Even when really fresh, as when we were getting it direct from the factory in Puerto Rico in the eighties, the effect wears off in a few months. The effect seems to improve utilization at the receptor site. The other problem is that the individual involved has the biochemistry of an alien and it could well be that this affect is a one off in their situation only. I'm sure we will probably never know.
I ordered a book by a doctor that is using ratios with T3 as Diogenes suggested and seems to be having good results. I'll let you know after I get a chance to digest it. It would seem that there is an almost infinite range of possible successful strategies. As we have talked about before, the longer it takes to get diagnosed and adequately treated the more damage that can be done. I think this is not understood well enough. PR
Definitely needs to be done. A shame that the obvious people do this, the manufacturers of desiccated thyroid products, either haven't done so or are unwilling to share their findings.
maggykriti, the treatment of choice should be whichever medicine relieves the symptoms and returns the patients sense of well being. I have a close family member who had a TT in 1969 and they have lived a good life on NDT, while it was absolute hell on T4. There are thousands with a similar story. Part of the trick is an adequate dose.
Much can be done with diet, lifestyle, proper exercise and supplements so I wouldn't condemn yourself just yet. I also do not think that science is working from a full understanding of many parts of the thyroid world including whether or not the other parts of NDT have an effect. Science has yet to study this adequately. Endocrinology continues to believe the myth that T4 works for everyone while thyroid patients know this is absolutely false, T4 works for some but not for all. Don't give up hope, your life might turn out better than you think. PR
Thanks PR4NOW. I am pretty good on NDT, now for 12 years. My concern is that by taking NDT I hoped I was replacing all the elements of a human thyroid, although in differing proportions. It is disappointing to read from Diogenes post that one of the elements, Calcitonin, is not thought to be absorbed orally even though present in the dessicated pig thyroid. No calcitonin coming from the thyroid gland is shown to lead to lowered bone mass and osteoporosis. However, since it is not bioavailable in NDT, replacing calcitonin requires medication which has side effects.
However, on the basis that, like your family member, I am quite well on NDT and a zombie on T4, NDT is my preference.
Like many I was told that after thyroidectomy it was straightforward to replace thyroid hormones orally. Clearly, this is not the case and nothing beats hanging on to your own thyroid!
Salmon calcitonin was available as a licensed medicine until it was withdrawn:
The product is being withdrawn throughout the European Union after a study has shown an increased risk of malignancies with the long term use of calcitonin. Both the Committee for Medicinal Products for Human Use (CHMP) and the Pharmacovigilance Risk Assessment Committee have concluded that the benefits no longer outweigh the risks.
Do we still need more trials on T4 and T3 combination therapy in hypothyroidism.Wilmar M Wiersinga. European Journal of Endocrinology; Dec.1, 2009, 161 955-959.
This paper suggests that a number of thyroid patients are carriers of polymorphisms in deiodinases and thyroid hormone transporters which are related to psychological well being
maggykriti, yes, this has come from the work of Dayan and others in England and has some traction in Europe but not much here in the USA with the official organizations. Another paper by Prof. Wiersinga in Jan.
T3 has gained experimental status in the European guidelines but again not in the USA guidelines. Prof. Wiersinga has a table (#3) showing the results of 6 crossover studies and 48% prefer combo therapy, 27% no preference and 25% prefer T4 monotherapy. PR
Thank you PR. Prof Wiersinga was suggesting that the preference for combination therapy may be related to being carriers of these polymorphisms which were found in 16% of thyroid patients. However, as you point out his crossover studies show that 48% have a preference for combination therapy which is a significant proportion of those taking part in the six studies. Polymorphism may explain some but not all of those preferring combination therapy.
maggykriti, science, in many aspects, is way behind the thyroid patient community. Science is just beginning to understand that there may be some legitimate reasons why T4 monotherapy doesn't work in all people. I've come to believe it is effective in only 20-25% of patients and that the rest could benefit from some T3. I wish science would do a better job of investigating why thyroid patients can react so differently to the various thyroid medications, however, I don't see that happening anytime soon. PR
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