Control of T4 and T3 amounts in NDT etc

Looking at the various posts, it seems that a whole raft of alternative NDTs and like preparations are being used for therapy. I'd like to know which of these are controlled by the standards set by a Pharmacopeia (that is they are effectively controlled drugs) and which are only classed as food supplements (not under any such strong control as to consistency of contents batch to batch). I think it would be useful to HU to classify the two sorts of NDT so as to be able to give advice on the safety and consistency of a particular product. It's essential for a patient to know exactly what they are taking, and how consistent it is; otherwise they can get into all sorts of trouble. Myself, I would only recommend Pharmacopeia controlled products as we know then what they contain.

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  • Diogenes, In the US, Armour (Armour Thyroid), RLC Labs (Nature-Throid and WP Thyroid) Acella Pharmaceuticals (NP Thyroid) are USP. In Canada Erfa Thyroid meets the Canadian equivalent to the USP. I don't know about the European or Mexican brands. Although Activis bought the Armour brand I don't know if they are changing the manufacturing site or what they intend to do with the brand. One would assume (hope) they will keep the brand and continue to meet USP standards. The 'Raw Glandulars' which are sold over the counter do not have any controls for content and as has been shown differ considerably. The one exception to this is Thyro-Gold which the late Dr. Lowe developed and is still being sold. Many people have reported success using this product but it is not USP. PR

    PS I know you have read and are familiar with Dr. Bianco's work but there are a couple of comments he makes in the presentation I posted that you might find interesting regarding thyroid output.

  • Diogenes,

    On the main Thyroid UK website, we have information about the prescription desiccated thyroid products that UK patients most commonly use. The information gives the ingredients and hormone content

    The ones listed are Nature-Throid, WP Thyroid, NP Thyroid, Thyroid (Erfa) and Armour.

    Here's the link

    thyroiduk.org.uk/tuk/treatm...

  • Thanks for the reassurance - thyroid patients have to be aware of the difference between controlled and uncontrolled products, as the latter are promoted rather irresponsibly in some countries without a real check on performance day to day. And not always for thyroid therapy either.

  • The "difficult" desiccated thyroid products in my mind are:

    The "glandulars". We read that they are pure thyroid powder with whatever else is necessary to make the final product. But the vendors usually claim they have no thyroid hormone content whatsoever. Followed by people who take them describing test results and effects that suggest they are rather weak and possibly variable products. If the vendors are right, where did the hormones go? I guess the vendors are trying to duck the legal controls that would apply if they did contain significant thyroid hormones.

    The Thai products - Thiroyd and Thyroid-S. Although widely regarded as quite effective, and seemingly quite popular, we have no official and up-to-date lists of ingredients, nor an adequately verified claim of potency. Many who take them suggest they are a little weaker than the main USA products.

    Rod

  • Re the Thai Products - I saw one today advertised on a website!

  • I'd like to know how levo was sneaked through with NO clinical trials at all!! NDT is made in the same process as any other medication and is as consistent. You need to stop listening to doctors and pharmaceutical reps as they are just in it for the money!!

  • Glynisrose, there were clinical trials and experiments since its discovery. What I have never been able to find are early trials (1940-1980s) comparing NDT versus levothyroxine. Please see my post below for an example. PR

  • There have been NO clinical trials for levo, that prove it works or not. NDT has been proved time and again to work so much better then T4 alone as it provides T1 T2 T3 and T4 it has had many trials and it is just down to the RCP and BTA to accept it now.

  • Well if you want to deny obvious evidence that's your prerogative.

  • Not denying anything, you can't deny what has never happened. You are one of those people who believes everything your doctor tells you, you'll learn.

  • I would put diogenes in the category of people who would have every reason to expect doctors to ask him questions and take his answers as gospel rather than him being told anything by doctors. (This is because of his intellectual background and experience - not because he is unwilling to listen if needed.)

  • I'm sorry to say that you are wrong. clinical trials have been done eg:

    Sem Hop. 1981 Mar 18-25;57(11-12):567-74.

    [Clinical trial of sodium levothyroxine in the treatment of hypothyroidism in adults (author's transl)].

    [Article in French]

    Charbonnel B, Guillon J.

    Pol Tyg Lek. 1989 Aug 7-14;44(32-33):768-70.

    [Comparative effects of desiccated thyroid gland and sodium salt of L-thyroxine in the treatment of hypothyroids

    This is not to say that I am in favour of T4 monotherapy as an answer to everyone's problems - it does not work for a significant minority especially those with no thyroid working and poor conversion of T4 to T3. But I work totally by evidence and not by unwarranted supposition. Both pharmacopeially controlled NDT and T4 are equally governed by strict rules. I don't disparage T4 where it works, but do recognize its limitations.

  • Diogenes,

    I have a study from 1950 by F. Dudley Hart and N. F. Maclagan BMJ March 4 1950 page 512 Title

    'Oral Thyroxine In Treatment of Myxoedema'. Although I'm not to sure about of couple of their conclusions, it is a rather interesting look at the early history. PR

    "The first report of the use of synthetic thyroxine in the treatment of myxoedema appeared as an addendum by Murray Lyon (1927) to the original paper by Harington and Barger (1927) describing the first synthesis of thyroxine. Two cases were treated, and their symptoms appeared to be satisfactori'y controlled for short periods by dosages of 4 to 5 mg. of the new drug, injected intravenously. Since then a number of workers have used thyroxine to treat myxoedema (Thompson, Thompson, and Dickie, 1933; Lerman and Salter, 1934; Means, 1935). Various routes of administration were tried and dosages varied from 0.3 to 1.5 mg. a day. More recently the activities of D- and L-thyroxine on human subjects have been compared

    by Pitt Rivers and Lerman (1948). In this study the drugs were administered by daily intravenous injections."

    The first versions must have been DL versions.

    "Recent developments in the synthesis of thyroxine (Borrows, Clayton, and Hems, 1949; Chalmers, Dickson, Elks, and Hems, 1949) seem to have altered the possible future of synthetic thyroxine. Although DL-thyroxine has been on the market for some years it appears to have

    been little used, and a new preparation of L-thyroxine sodium has now appeared. It seems likely that in the future the price of synthetic thyroxine may well be able to compete with that of thyroid extract."

  • Something of an irony that synthetic levothyroxine is now so incredibly inexpensive (at least in the UK where we don't have AbbVie pushing over-priced Synthroid). And desiccated thyroid is so much more expensive here.

    Something of an indictment that the possible future price seems so important a justification for levothyroxine when there was already a reasonable treatment available. (Though let us not fool ourselves that desiccated thyroid has always been as well regulated as now.)

    Rod

  • Rod, Armour had always been the Cadillac of NDT preparations. My family has been using it since about 1927. Some of the brands however were no better than taking cement pills. Even using iodine as the measure of content, I know of no reports from early 1900s up to the great thyroid hoax of the 1960s that complained of problems with Armour, that were substantiated. There were stories of problems with other brands.

    If the NDT brands were listed, imported and used legally, like they were before 1978, I bet the price would be much cheaper. In the early 1970s before the ban my relative tells me that Armour was available at all the chemists. In fact there were several brands of NDT, some of which were known to be junk. PR

  • Have long suspected that we continue to reap what the charlatans sowed - the reputation of desiccated thyroid (such as it has in the UK) seems more in line with the cement pills than the Cadillac. That seems to have become the widespread opinion of the medical establishment even with the far better quality control now in place.

    I know almost nothing about Thyroid BP over here. No idea how many companies were involved or the quality of the products.

    Rod

  • There were plenty of trials to validate the use of T4, but as you point out, the quality of those trials in the past was not up to the standard requirements of today. Cochrane was instrumental in demanding properly controlled randomized trials for discovering the efficacy of drugs or treatment., methods which are now standard for credible trialling. I too didn't realize that DL-T4 was the first material used - thank goodness D-T4 is harmless though not an active hormone. However as regards the value of T2 and T1 in NDT I'm very sceptical. First T2 and T1 are largely produced by extrathyroidal peripheral tissues and not by the thyroid itself, and secondly the amount of T2 in NDT doses is small compared with the body's daily requirements. So even if one had no thyroid, T2/1 will be produced by the periphery. I would think even in those people who need T3 in some form, T2 production in vivo would be adequate.

  • Here is a reference which at least dates the time of switching from unreliable NDT assays using iodine content to at least a better method. I myself can only get the precis.

    A New Synthetic Thyroid Hormone Combination for Clinical Therapy

    HERBERT A. SELENKOW, M.D., F.A.C.P.; and MARVIN S. WOOL, M.D.

    Ann Intern Med. 1967;67(1):90-99. doi:10.7326/0003-4819-67-1-90

  • First page (using optical character recognition and manual correction):

    A New Synthetic Thyroid Hormone Combination for Clinical Therapy

    HERBERT A. SELENKOW, M.D., F.A.C.P., and MARVIN S. WOOL, M.D.

    Boston

    THYROID HORMONE PREPARATIONS of animal origin have been used extensively for over three quarters of a century. Their striking metabolic effects in correcting human thyroid insufficiency are well-known to physicians, and their therapeutic use in suppression of goiter as well as in non- thyroidal metabolic disorders is common practice. Less appreciated, however, are the variations in potency and hormonal constitution that may occur among preparations derived from the same or from different animal species or that are a consequence of a particular method of processing. Widely varying or even impotent preparations of commercially available thyroid can still conform to U. S. Pharmacopeia (USP) specifications. This results directly from inadequacies in the current method of standardization. In recent years, several large manufacturers of animal thyroid have supplemented chemical standardization with bioassay and have thus improved the quality and uniformity of their product.

    In view of pharmaceutical problems associated with desiccated thyroid USP and in view of the ready availability of synthetic I-thyroxine (I-T4) and I-triiodothyronine (l-T3) it seemed logical to develop a combination of these hormones of comparable composition as in thyroglobulin. Such a preparation would have the advantage of containing quantitatively exact amounts of synthetically pure I-T4 and l-T3 formulated to simulate the metabolic actions of endogenous thyroid gland secretions. This report presents further observations supporting the clinical efficacy of such a synthetic thyroid hormone combination.

    METHODS AND MATERIALS

    A group of 57 patients with primary myxedema of various etiologies and 6 patients with pituitary myxedema were treated on an outpatient basis, Their ages varied between 14 and 80 years (mean 47 years). In addition, other treatment groups included patients with nontoxic goiter, normal and goitrous pregnancy, and hyperthyroidism treated with a combination of antithyroid drugs and thyroid.

    annals.org/article.aspx?art...

    Please advise me if I have missed any mistakes.

    Rod

  • Thank you for that. I am obviously not conversant with all the discussions in HU, being a bit of a "Johnny come lately" but I do feel this objective toing and froing of information must be of some help, if only to crystallise the history of what actually happened, how and why NDT was replaced by T4, the raionalisation for that, and the consequences. I think that if HU develops a good unrefutable historical archive of events (but valuable and spurious) then the naysayers will have to put up or shut up. My view is the more info you have the better equipped you are to refute unsupportable allegations. This is the only viable way to challenge the medical establishment's present stance - by data, data, data, fact, fact, fact. Dull I fear but the only grinding way forward..

  • This group has now achieved one of the things that seemed impossible in its early days: combining individual patient support and serious discussion of the scientific/medical issues - and lots else besides.

    I certainly don't think of you as a "Johnny come lately" - and your contributions are always appreciated. Few of us here (certainly not me!) have the scientific backgrounds to understand things deeply enough.

    Rod

  • I think the HU signature tune should be Frank Sinatra's song"High Hopes".

  • Diogenes, in that case Levothyroxine's should be Peggy Lee's "Is that all there is?" ;)

    azlyrics.com/lyrics/peggyle...

  • Good one!!! And the usual response from your doctor about being in the "normal" range could be "Jive Talking" from the Bee Gees, of course that would also especially qualify for when you're told that you suffer from 'Somatoform Disorder'. PR

    "It's just you're jive talkin you're telling me lies, yeah

    Jive talkin, you wear a disguise

    Jive talkin, so misunderstood, yeah

    Jive talkin, you're really no good"

  • PR4Now :-D

    I forsee a surge in psych referrals as hypo patients walk into GP/endo appts full of hope singing "High Hopes", followed by "Is that all there is" when prescribed Levothyroxine and exit singing "Jive Talking" when told symptoms are not thyroidal.

    A member's endo told her to get a pysch referral. Her pysch said there's nothing wrong with her head and to tell the endo to get her thyroid meds right.

  • Diogenes, "In recent years, several large manufacturers of animal thyroid have supplemented chemical standardization with bioassay and have thus improved the quality and uniformity of their product." The chemical standardization would have been measuring iodine. Would the 'bioassay' part have been measuring T4 and T3? Were the bioassays accurate enough in 1967 to do that? PR

  • Not good enough quantitatively but better than measuring iodine only. At least they were relating content of hormone to biological response in an animal model.

  • Diogenes,

    While cruising the web looking up the references you listed I found the patent for making T3 by Gross and Pitt-Rivers which has this statement. Didn't realize they had looked at the D and L versions so closely back then. PR

    "Naturally 'occurring thyroxine is L-thyroxine and this form is considerably more active than D-thyroxine. Pitt-Rivers and Lerman (1948) Journal of Endocrinology, volume 5, page 223, have shown that L-thyroxine is 8 to 10 times more active than D-thyroxine in restoring the basal metabolic rate in myxoedema patients to normal levels. e

    Naturally occurring tri-iodothyronine is L-tri-iodo-thyronine. 'The L- and D-isomers have been synthesised, and it has been shown that the D-isomer only possesses about 7% of the activity of the'L-isomer in the goitre prevention test in rats. DL-tri-iodo-thyronine prepared by the method of Roche, Lissitzky and Michel (1952) C. R. Acad. Sci., Paris, 234, 997, only possesses about one-half of the activity of the L-isomer, in the same biological assay. v

    L-tri-iodothyronine has also been'shown to possess about 5 times the activity of L-thyroxine in the goitre prevention assay in rats and an increased activity of the same order in restoring the basal metabolic rates and blood cholesterol levels of myxoedema patients to normal values."

    Forgot to add the link, oops. PR

    google.com/patents/US2823164

  • Is there any early research that compares symptom relief when taking animal thyroid products and symptom relief when taking artificial thyroxine?

    One of the biggest issues for people who don't respond to levothyroxine is that the medical profession will often totally dismiss all information about symptoms. Only the blood tests count. If we complain of ongoing symptoms then we must be liars and can safely be dismissed, often with a prescription for anti-depressants or anti-anxiety medication. Or alternatively, each symptom is taken individually and treated as a different problem, not as part and parcel of a thyroid diagnosis.

    My French isn't up to the task of reading a scientific article in the language. But the English paper you linked to just refers to blood test results to make a conclusion.

  • The problem with the early research I think was that the objective was merely to be able to say that synthetic T4 could take the place of NDT. Comparisons I think were sparse - as a chemist by training I can see where the researchers were coming from: NDT at that time was not well controlled, so why not replace with a wellknown substance T4 that is chemically pure, "so that we know what it is doing". That, mea culpa, would be my position if I didn't realise that things are a lot more complicated than that. At the time, the idea that pure reproducible T4 could replace with advantage impure, variable NDT was irresistible. And for a lot of people it worked, but a good minority were left behind and the science then simply wasn't up to it to understand or even tolerate why. There is a pernicious idea in biology: it's called reductionism. that is, to look at the human body like a Newtonian mechanical clock - constant, unchanging and universal. And now we know that, in all situations, this isn't so: there are many routes to health within set limits of variation in any parameter, and therefore the implications when things go wrong are equally variable especially when trying by treatment to return to something like a healthy state. This does not just apply to thyroid, but to all parameters. That's why the statistical approach to diagnosis: are you within or outside the "reference range" is not strictly appropriate. How can I put it better: the anecdote does not define the population, but neither does the population define the anecdote.

  • But the statistical approach to diagnosis only seems to be used in certain illnesses and conditions.

    An anecdote...

    My father, back in the late 80s or early 90s, was diagnosed with high blood pressure. He suffered severe side effects on the first treatment. So it was changed, then changed again. In total it took nearly 2 years and five different treatment protocols before his blood pressure was reduced AND his side effects were tolerable. This wasn't considered odd by his doctor nor did he assume my father was attention-seeking or depressed or anxious or mad.

    Contrast the above experience with thyroid treatment for so many, and the difference is stark. Symptoms and side effects count for nothing. If you don't tolerate synthetic levothyroxine then you are clearly deranged.

    I did read one paper looking at symptoms - this one published online March 2013 :

    press.endocrine.org/doi/abs...

    where 48.6% of people preferred animal thyroid treatment, 32.9% had no preference, and 18.6% preferred levothyroxine.

    The conclusion?

    "DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTE over l-T4. DTE therapy may be relevant for some hypothyroid patients."

    This conclusion is a whitewash of their own results. If nearly 50% preferred DTE then clearly it did give a significant improvement in quality of life. So how can they possibly say otherwise? Just because being hypothyroid makes some people gain weight doesn't mean that is all they care about. You mentioned reductionism. I think the conclusion of this paper is reductionism taken to absurd levels.

    I think my problem, and the problem of so many of us, is simply understanding why thyroid treatment is treated so very differently from, for instance, high blood pressure and diabetes. Diabetics require insulin. So why are there over 80 entries in the BNF for medications related to diabetes and its side effects. For hypothyroidism there are 2 - levothyroxine and liothyronine - with a couple of sub-types accounting for the need for liquid and injectable preparations of these two treatments. That is all. There is no logic to this so many of us start building conspiracy theories. And sometimes I have a lot of sympathy with them!

  • When I read that paper, I too had the same reaction. With more thought, I concluded that what they were actually saying was that the difference in quality of life as they measured it was not statistically significant.

    I think the authors were well aware that their measurements of quality of life were limited. I also believe that they are at least now aware that their doses of desiccated were (arguably) too low. With a better quality of life assessment and a slightly higher dosing with desiccated, the results might well be different.

    Did I read that they were going on to a larger and longer trial?

    Rod

  • The paper's conclusion is certainly questionable. Eg the total T3 (they didn't do FT3 but you can do total for normal average people) in NDT was significantly higher than with T4 monotherapy, which actually put the T3 quite close to the lower part of the reference range. T3 with NDT was sightly above average but still appeared normal. The perennial problem is always that one can never know where the patients were in the reference ranges for T3 when they were well. On the average about 17-20% of people at random will have normal T3's in the lower third of the reference range - their healthy level. So we'd expect these people to be OK on T4 only, because it gives them a reasonable T3 (FT3). So at random I'd expect up to 20% of people who may prefer T4 in QoL, if FT3 levels are the yardstick. The rest will need higher levels of T3 to be satisfied, and it may be these at random who benefit. Lets say all those whose normal T3 is above the midpoint of the reference range (i.e. 50%). The ones in between the low T3 and high T3 may be indifferent one way or the other.

  • Diogenes, if I read this correctly you are saying that the lower 20% of the reference range (T3) should do fine on T4 only, the next 30% may be indifferent and the top 50% would probably prefer more T3. That is remarkably close to Prof. Wiersinga's table 3 from his Jan 2014 paper which looked at six double blind crossover studies of T4 mono versus combo therapy. The numbers from his table showed 25% preferred T4 mono, 27% no preference and 48% preferred combo therapy.

    If these numbers are reasonably accurate then the standard starting point should be NDT since it would cover 75% of the population whereas starting with T4 mono therapy only covers 52% of the patient population. PR

  • What I did was no more than a proposition without real evidence. I argued that the lower 20% in the T3 normal range for healthy people are obviously those who are good converters and can readily use their T3 at a lower equilibrium level of supply than the others. The next 30% get us through the T3 range up to the peak of distribution (the T3 level where most people are). These are the ones going through from good to average converters. The last 50% are those above the peak, that is they need more T3 to operate and those are the average to poorer converters - the top 20% of these could be the poorest. Thus I made my supposition on how they might respond to T4 or T3 therapy. It's only a suggestion, hampered by the fact that one doesn't know what FT3 the subjects had before therapy was needed. But the idea is at least plausible if not provable.

  • Diogenes, I agree with your synopsis, I think the intentions were good, just lacking in any real in-depth understanding of the total system. One fallacy I've noticed on the patient forums is that people tend to think that before the TSH test there were no problems getting diagnosed and treated. That actually is far from the truth, accuracy of diagnosis and adequate treatment have been a problem for a long time. My mother was diagnosed about 1927 and put on a dose of 1/4 grain and left at that dose for the next 55 years of her life. She paid a terrible price for that and never had a chance for a 'normal' life. My father, who had obvious problems on the thyroid/ adrenal axis, never was diagnosed even though he had classic signs and symptoms. His secret weapon were his recliners, one at home and one at work. He was 'power napping' before they knew what it was. Even though he had 3 heart attacks in the 1960s they never put 2 + 2 together. For those patients that were diagnosed and treated by slowly titrating the dose upward until the symptoms disappeared and the patient felt well, they actually did very well and led normal lives. But an accurate diagnosis and adequate treatment were anything but guaranteed. Also the average normal dose was 2-3 times greater than after the TSH test with no studies showing that patients were dropping like flies from being overdosed. Hopefully your study that is under review will shed some light on why most of us on NDT do not show the expected hyper symptoms or effects that science thinks we should show. PR

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