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Written by Dr. John Lowe, MA, DC and The Thyroid Patient Advocacy UK http://thyroidscience.com/Criticism/lowe.dec.2006/lowe.critique.T4.T4.T3.studies.pdf Dr. John C. Lowe, a long-time researcher into hypothyroidism, hypometabolism, fibromyalgia, and the use of T3 drugs for thyroid and metabolic conditions, has published a groundbreaking, must-read analysis. He has looked at the four studies published recently in major medical journals, all of which were blanketly critical of the use of T3. Dr. Lowe has deconstructed the research, and pointed out the numerous major flaws — flaws that will force your physician to rethink the validity of the earlier findings. For any thyroid patient who doesn’t feel well on T4 (levothyroxine, i.e., Synthroid) alone, I urge you to print off the PDF version of the analysis report, and bring it to your physician. And if you have a doctor or endocrinologist who has dismissed T3 because of the recent research, then even more reason to make sure you share a copy of Dr. Lowe’s paper, Thyroid Hormone Replacement Therapies: Ineffective and Harmful for Many Hypothyroid Patients. You can also read an html version online. Now, a special message from Dr. Lowe: Some six months ago, medical journals published four studies by endocrinologists that piqued attention in the alternative medicine community. In the studies, the endocrinologists compared the effectiveness of T4-replacement with that of combined T4/T3-replacement. “Replacement,” of course, refers to doses of thyroid hormone that keep the TSH level within its current lab reference range. Keeping this definition in mind is crucial to understanding what the four studies actually showed, and what they didn’t show. What the studies showed is this: Neither form of replacement therapy relieved hypothyroid patients’ symptoms or abnormal test results. In fact, the four studies are proof positive that replacement therapies leave many hypothyroid patients suffering. Most of the researchers accurately reported this negative treatment finding. However, the finding is buried deeply within their full-text published reports; to see that it’s there, one must first get a copy of the journal articles — which most doctors and patients won’t do — and then read carefully. In contrast to what they did find, the endocrinologists clearly broadcast something they did not find: that no approach to T4/T3 therapy is more effective than T4 alone. As I explain in detail in my critique, the difference between what they did find and what they didn’t find is no minor distinction; it can seriously impact the clinical care of hypothyroid patients. The false reports of the endocrinologists are almost certain to implant a false belief in the minds of doctors. As a result, the doctors are likely to restrict millions of hypothyroid patients to T4-replacement despite the studies showing that it’s ineffective for many patients. The four studies appeared to be a response by the endocrinology specialty and its corporate sponsors to a study published in 1999 in the New England Journal of Medicine.[1] In that study, researchers reported a finding that threatened the market for T4-replacement therapy. The finding was that adding T3 to hypothyroid patients’ daily T4 dose improved their cognitive function. As a result of that study, many hypothyroid patients began asking their doctors to add T3 to the T4 they were already taking. The result of the four 2003 studies –that combined T4/T3-replacement was no more effective than T4-replacement — contradicts the result of the 1999 study. A few alternative thyroid doctors criticized some of the 2003 studies. The main place their criticisms were published was thyroid.about.com — the website of thyroid patient advocate Mary Shomon, where the democratic spirit is exercised by publication of dissenting views. However, no criticism of the studies was published in any major medical journal. This was certainly no surprise to us at the Fibromyalgia Research Foundation. Our research team learned long ago that the pages of major medical journals are almost always closed to thyroid researchers except under one condition: when they’re reporting study results that support the prejudice of the endocrinology specialty in favor of T4-replacement. If a research team’s study finding isn’t favorable to T4-replacement, the team might as well forget submitting the report to any major medical journal — it’s extremely unlikely that it would be accepted for publication. A truly rare exception was the 1999 study reporting that T4/T3 replacement was more effective than T4 replacement. I’m still wondering how that report slipped past the endocrinology specialty’s censors. The main editorials on the four 2003 studies in major medical journals were written by endocrinologists. In each of the editorials, the endocrinologists echoed the false reports of the endocrinologists who conducted the studies. We’ve published my critique of the four studies at drlowe.com. The critique is a formal logical analysis with ethical implications. The purpose of the critique is three-fold: (1) to explain the fallacy in the endocrinology researchers’ reports; (2) to give evidence that for many patients, T4-replacement is both ineffective and harmful; and (3) to question the endocrinologists’ motive in advising that T4-replacement remain the treatment of choice, despite the studies showing it to be ineffective in relieving many patients’ symptoms. I am sending notice of the critique to these endocrinology researchers and the endocrinologists who wrote editorials repeating the false conclusion. We’ll let our readers know the content of any replies I receive from them. I want to thank my Editor, Jackie Yellin, for working long and hard with me to make the critique clear and logically precise. Also, I want to thank Michael Yellin for his fastidious proof-reading. I also thank Mary Shomon for notifying her readers about the critique. She tells me that she’ll advise patients who are restricted to T4-replacement and still suffering from hypothyroid symptoms to print the critique as a pdf file and take it to their prescribing doctors. Doctors who read it will know why their patients continue to suffer from hypothyroid symptoms despite using T4-replacement. The doctors will also be aware that restricting their patients to T4-replacement may increase their drug use and put them at risk for several diseases that can lead to their premature death. Reference [1] Bunevicius, R., Kazanavicius, G., Zalinkevicius, R., and Prange, A.J. Jr.: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N. Engl. J. Med., 11;340(6):424-429, 1999.

Written by Dr. Ray Peat, 2006 I. Respiratory-metabolic defect II. 50 years of commercially motivated fraud III. Tests and the “free hormone hypothesis” IV. Events in the tissues V. Therapies VI. Diagnosis I. Respiratory defect Broda Barnes, more than 60 years ago, summed up the major effects of hypothyroidism on health very neatly when he pointed out that if hypothyroid people don’t die young from infectious diseases, such as tuberculosis, they die a little later from cancer or heart disease. He did his PhD research at the University of Chicago, just a few years after Otto Warburg, in Germany, had demonstrated the role of a “respiratory defect” in cancer. At the time Barnes was doing his research, hypothyroidism was diagnosed on the basis of a low basal metabolic rate, meaning that only a small amount of oxygen was needed to sustain life. This deficiency of oxygen consumption involved the same enzyme system that Warburg was studying in cancer cells. Barnes experimented on rabbits, and found that when their thyroid glands were removed, they developed atherosclerosis, just as hypothyroid people did. By the mid-1930s, it was generally known that hypothyroidism causes the cholesterol level in the blood to increase; hypercholesterolemia was a diagnostic sign of hypothyroidism. Administering a thyroid supplement, blood cholesterol came down to normal exactly as the basal metabolic rate came up to the normal rate. The biology of atherosclerotic heart disease was basically solved before the second world war. Many other diseases are now known to be caused by respiratory defects. Inflammation, stress, immunodeficiency, autoimmunity, developmental and degenerative diseases, and aging, all involve significantly abnormal oxidative processes. Just brief oxygen deprivation triggers processes that lead to lipid peroxidation, producing a chain of other oxidative reactions when oxygen is restored. The only effective way to stop lipid peroxidation is to restore normal respiration. Now that dozens of diseases are known to involve defective respiration, the idea of thyroid’s extremely broad range of actions is becoming easier to accept. II. 50 years of fraud Until the second world war, hypothyroidism was diagnosed on the basis of BMR (basal metabolic rate) and a large group of signs and symptoms. In the late 1940s, promotion of the (biologically inappropriate) PBI (protein-bound iodine) blood test in the U.S. led to the concept that only 5% of the population were hypothyroid, and that the 40% identified by “obsolete” methods were either normal, or suffered from other problems such as sloth and gluttony, or “genetic susceptibility” to disease. During the same period, thyroxine became available, and in healthy young men it acted “like the thyroid hormone.” Older practitioners recognized that it was not metabolically the same as the traditional thyroid substance, especially for women and seriously hypothyroid patients, but marketing, and its influence on medical education, led to the false idea that the standard Armour thyroid USP wasn’t properly standardized, and that certain thyroxine products were; despite the fact that both of these were shown to be false. By the 1960s, the PBI test was proven to be irrelevant to the diagnosis of hypothyroidism, but the doctrine of 5% hypothyroidism in the populaton became the basis for establishing the norms for biologically meaningful tests when they were introduced. Meanwhile, the practice of measuring serum iodine, and equating it with “thyroxine the thyroid hormone,” led to the practice of examining only the iodine content of the putative glandular material that was offered for sale as thyroid USP. This led to the substitution of materials such as iodinated casein for desiccated thyroid in the products sold as thyroid USP. The US FDA refused to take action, because they held that a material’s iodine content was enough to identify it as “thyroid USP.” In this culture of misunderstanding and misrepresentation, the mistaken idea of hypothyroidism’s low incidence in the population led to the acceptance of dangerously high TSH (thyroid stimulating hormone) activity as “normal.” Just as excessive FSH (follicle stimulating hormone) has been shown to have a role in ovarian cancer, excessive stimulation by TSH produces disorganization in the thyroid gland. III. Tests & the “free hormone hypothesis” After radioactive iodine became available, many physicians would administer a dose, and then scan the body with a Geiger counter, to see if it was being concentrated in the thyroid gland. If a person had been eating iodine-rich food (and iodine was used in bread as a preservative/dough condition, and was present in other foods as an accidental contaminant), they would already be over saturated with iodine, and the gland would fail to concentrate the iodine. The test can find some types of metastatic thyroid cancer, but the test generally wasn’t used for that purpose. Another expensive and entertaining test has been the thyrotropin release hormone (TRH) test, to see if the pituitary responds to it by increasing TSH production. A recent study concluded that “TRH test gives many misleading results and has an elevated cost/benefit ratio as compared with the characteristic combination of low thyroxinemia and non-elevated TSH.” (Bakiri, Ann. Endocr (Paris) 1999), but the technological drama, cost, and danger (Dokmetas, et al., J Endocrinol Invest 1999 Oct; 22(9): 698-700) of this test is going to make it stay popular for a long time. If the special value of the test is to diagnose a pituitary abnormality, it seems intuitively obvious that overstimulating the pituitary might not be a good idea (e.g., it could cause a tumor to grow). Everything else being equal, as they say, looking at the amount of thyroxine and TSH in the blood can be informative. The problem is that it’s just a matter of faith that “everything else” is going to be equal. The exceptions to the “rule” regarding normal ranges for thyroxine and TSH have formed the basis for some theories about “the genetics of thyroid resistance,” but others have pointed out that, when a few other things are taken into account, abnormal numbers for T4, T3, TSH, can be variously explained. The actual quantity of T3, the active thyroid hormone, in the blood can be measured with reasonable accuracy (using radioimmunoassay, RIA), and this single test corresponds better to the metabolic rate and other meaningful biological responses than other standard tests do. But still, this is only a statistical correspondence, and it doesn’t indicate that any particular number is right for a particular individual. Sometimes, a test called the RT3U, or resin T3 uptake, is used, along with a measurement of thyroxine. A certain amount of radioactive T3 is added to a sample of serum, and then an adsorbent material is exposed to the mixture of serum and radioactive T3. The amount of radioactivity that sticks to the resin is called the T3 uptake. The lab report then gives a number called T7, or free thyroxine index. The closer this procedure is examined, the sillier it looks, and it looks pretty silly on its face.. The idea that the added radioactive T3 that sticks to a piece of resin will correspond to “free thyroxine,” is in itself odd, but the really interesting question is, what do they mean by “free thyroxine”? Thyroxine is a fairly hydrophobic (insoluble in water) substance, that will associate with proteins, cells, and lipoproteins in the blood, rather than dissolving in the water. Although the Merck Index describes it as “insoluble in water,” it does contain some polar groups that, in the right (industrial or laboratory) conditions, can make it slightly water soluble. This makes it a little different from progesterone, which is simply and thoroughly insoluble in water, though the term “free hormone” is often applied to progesterone, as it is to thyroid. In the case of progesterone, the term “free progesterone” can be traced to experiments in which serum containing progesterone (bound to proteins) is separated by a (dialysis) membrane from a solution of similar proteins which contain no progesterone. Progesterone “dissolves in” the substance of the membrane, and the serum proteins, which also tend to associate with the membrane, are so large that they don’t pass through it. On the other side, proteins coming in contact with the membrane pick up some progesterone. The progesterone that passes through is called “free progesterone,” but from that experiment, which gives no information on the nature of the interactions between progesterone and the dialysis membrane, or about its interactions with the proteins, or the proteins’ interactions with the membrane, nothing is revealed about the reasons for the transmission or exchange of a certain amount of progesterone. Nevertheless, that type of experiment is used to interpret what happens in the body, where there is nothing that corresponds to the experimental set-up, except that some progesterone is associated with some protein. The idea that the “free hormone” is the active form has been tested in a few situations, and in the case of the thyroid hormone, it is clearly not true for the brain, and some other organs. The protein-bound hormone is, in these cases, the active form; the associations between the “free hormone” and the biological processes and diseases will be completely false, if they are ignoring the active forms of the hormone in favor of the less active forms. The conclusions will be false, as they are when T4 is measured, and T3 ignored. Thyroid-dependent processes will appear to be independent of the level of thyroid hormone; hypothyroidism could be caller hyperthyroidism. Although progesterone is more fat soluble than cortisol and the thyroid hormones, the behavior of progesterone in the blood illustrates some of the problems that have to be considered for interpreting thyroid physiology. When red cells are broken up, they are found to contain progesterone at about twice the concentration of the serum. In the serum, 40 to 80% of the progesterone is probably carried on albumin. (Albumin easily delivers its progesterone load into tissues.) Progesterone, like cholesterol, can be carried on/in the lipoproteins, in moderate quantities. This leaves a very small fraction to be bound to the “steroid binding globulin.” Anyone who has tried to dissolve progesterone in various solvents and mixtures knows that it takes just a tiny amount of water in a solvent to make progesterone precipitate from solution as crystals; its solubility in water is essentially zero. “Free” progesterone would seem to mean progesterone not attached to proteins or dissolved in red blood cells or lipoproteins, and this would be zero. The tests that purport to measure free progesterone are measuring something, but not the progesterone in the watery fraction of the serum. The thyroid hormones associate with three types of simple proteins in the serum: Transthyretin (prealbumin), thyroid binding globulin, and albumin. A very significant amount is also associated with various serum lipoproteins, including HDL, LDL, and VLDL (very low density lipoproteins). A very large portion of the thyroid in the blood is associated with the red blood cells. When red cells were incubated in a medium containing serum albumin, with the cells at roughly the concentration found in the blood, they retained T3 at a concentration 13.5 times higher than that of the medium. In a larger amount of medium, their concentration of T3 was 50 times higher than the medium’s. When laboratories measure the hormones in the serum only, they have already thrown out about 95% of the thyroid hormone that the blood contained. The T3 was found to be strongly associated with the cells’ cytoplasmic proteins, but to move rapidly between the proteins inside the cells and other proteins outside the cells. When people speak of hormones travelling “on” the red blood cells, rather than “in” them, it is a concession to the doctrine of the impenetrable membrane barrier. Much more T3 bound to albumin is taken up by the liver than the small amount identified in vitro as free T3 (Terasaki, et al., 1987). The specific binding of T3 to albumin alters the protein’s electrical properties, changing the way the albumin interacts with cells and other proteins. (Albumin becomes electrically more positive when it binds the hormone; this would make the albumin enter cells more easily. Giving up its T3 to the cell, it would become more negative, making it tend to leave the cell.) This active role of albumin in helping cells take up T3 might account for its increased uptake by the red cells when there were fewer cells in proportion to the albumin medium. This could also account for the favorable prognosis associated with higher levels of serum albumin in various sicknesses. When T3 is attached chemically (covalently, permanently) to the outside of red blood cells, apparently preventing its entry into other cells, the presence of these red cells produces reactions in other cells that are the same as some of those produced by the supposedly “free hormone.” If T3 attached to whole cells can exert its hormonal action, why should we think of the hormone bound to proteins as being unable to affect cells? The idea of measuring the “free hormone” is that it supposedly represents the biologically active hormone, but in fact it is easier to measure the biological effects than it is to measure this hypothetical entity. Who cares how many angels might be dancing on the head of a pin, if the pin is effective in keeping your shirt closed? IV. Events in the tissues Besides the effects of commercial deception, confusion about thyroid has resulted from some biological clichs. The idea of a “barrier membrane” around cells is an assumption that has affected most people studying cell physiology, and its effects can be seen in nearly all of the thousands of publications on the functions of thyroid hormones. According to this idea, people have described a cell as resembling a droplet of a watery solution, enclosed in an oily bag which separates the internal solution from the external watery solution. The clich is sustained only by neglecting the fact that proteins have a great affinity for fats, and fats for proteins; even soluble proteins, such as serum albumin, often have interiors that are extremely fat-loving. Since the structural proteins that make up the framework of a cell aren’t “dissolved in water” (they used to be called “the insoluble proteins”), the lipophilic phase isn’t limited to an ultramicroscopically thin surface, but actually constitutes the bulk of the cell. Molecular geneticists like to trace their science from a 1944 experiment that was done by Avery., et al. Avery’s group knew about an earlier experiment, that had demonstrated that when dead bacteria were added to living bacteria, the traits of the dead bacteria appeared in the living bacteria. Avery’s group extracted DNA from the dead bacteria, and showed that adding it to living bacteria transferred the traits of the dead organisms to the living. In the 1930s and 1940s, the movement of huge molecules such as proteins and nucleic acids into cells and out of cells wasn’t a big deal; people observed it happening, and wrote about it. But in the 1940s the idea of the barrier membrane began gaining strength, and by the 1960s nothing was able to get into cells without authorization. At present, I doubt that any molecular geneticist would dream of doing a gene transplant without a “vector” to carry it across the membrane barrier. Since big molecules are supposed to be excluded from cells, it’s only the “free hormone” which can find its specific port of entry into the cell, where another clich says it must travel into the nucleus, to react with a specific site to activate the specific genes through which its effects will be expressed. I don’t know of any hormone that acts that way. Thyroid, progesterone, and estrogen have many immediate effects that change the cell’s functions long before genes could be activated. Transthyretin, carrying the thyroid hormone, enters the cell’s mitochondria and nucleus (Azimova, et al., 1984, 1985). In the nucleus, it immediately causes generalized changes in the structure of chromosomes, as if preparing the cell for major adaptive changes. Respiratory activation is immediate in the mitochondria, but as respiration is stimulated, everything in the cell responds, including the genes that support respiratory metabolism. When the membrane people have to talk about the entry of large molecules into cells, they use terms such as “endocytosis” and “translocases,” that incorporate the assumption of the barrier. But people who actually investigate the problem generally find that “diffusion,” “codiffusion,” and absorption describe the situation adequately (e.g., B.A. Luxon, 1997; McLeese and Eales,1996). “Active transport” and “membrane pumps” are ideas that seem necessary to people who haven’t studied the complex forces that operate at phase boundaries, such as the boundary between a cell and its environment. V. Therapy Years ago it was reported that Armour thyroid, U.S.P., released T3 and T4, when digested, in a ratio of 1:3, and that people who used it had much higher ratios of T3 to T4 in their serum, than people who took only thyroxine. The argument was made that thyroxine was superior to thyroid U.S.P., without explaining the significance of the fact that healthy people who weren’t taking any thyroid supplement had higher T3:T4 ratios than the people who took thyroxine, or that our own thyroid gland releases a high ratio of T3 to T4. The fact that the T3 is being used faster than T4, removing it from the blood more quickly than it enters from the thyroid gland itself, hasn’t been discussed in the journals, possibly because it would support the view that a natural glandular balance was more appropriate to supplement than pure thyroxine. The serum’s high ratio of T4 to T3 is a pitifully poor argument to justify the use of thyroxine instead of a product that resembles the proportion of these substances secreted by a healthy thyroid gland, or maintained inside cells. About 30 years ago, when many people still thought of thyroxine as “the thryoid hormone,” someone was making the argument that “the thyroid hormone” must work exclusively as an activator of genes, since most of the organ slices he tested didn’t increase their oxygen consumption when it was added. In fact, the addition of thyroxine to brain slices suppressed their respiration by 6% during the experiment. Since most T3 is produced from T4 in the liver, not in the brain, I think that experiment had great significance, despite the ignorant interpretation of the author. An excess of thyroxine, in a tissue that doesn’t convert it rapidly to T3, has an antithyroid action. (See Goumaz, et al, 1987.) This happens in many women who are given thyroxine; as their dose is increased, their symptoms get worse. The brain concentrates T3 from the serum, and may have a concentration 6 times higher than the serum (Goumaz, et al., 1987), and it can achieve a higher concentration of T3 than T4. It takes up and concentrates T3, while tending to expel T4. Reverse T3 (rT3) doesn’t have much ability to enter the brain, but increased T4 can cause it to be produced in the brain. These observations suggest to me that the blood’s T3:T4 ratio would be very “brain favorable” if it approached more closely to the ratio formed in the thyroid gland, and secreted into the blood. Although most synthetic combination thyroid products now use a ratio of four T4 to one T3, many people feel that their memory and thinking are clearer when they take a ratio of about three to one. More active metabolism probably keeps the blood ratio of T3 to T4 relatively high, with the liver consuming T4 at about the same rate that T3 is used. Since T3 has a short half life, it should be taken frequently. If the liver isn’t producing a noticeable amount of T3, it is usually helpful to take a few micorgrams per hour. Since it restores respiration and metabolic efficiency very quickly, it isn’t usually necessary to take it every hour or two, but until normal temperature and pulse have been achieved and stabilized, sometimes it’s necessary to take it four or more times during the day. T4 acts by being changed to T3, so it tends to accumulate in the body, and on a given dose, usually reaches a steady concentration after about two weeks. An effective way to use supplements is to take a combination T4-T3 dose, e.g., 40 mcg of T4 and 10 mcg of T3 once a day, and to use a few mcg of T3 at other times in the day. Keeping a 14-day chart of pulse rate and temperature allows you to see whether the dose is producing the desired response. If the figures aren’t increasing at all after a few days, the dose can be increased, until a gradual daily increment can be seen, moving toward the goal at the rate of about 1/14 per day VI. Diagnosis In the absence of commercial techniques that reflect thyroid physiology realistically, there is no valid alternative to diagnosis based on the known physiological indicators of hypothyroidism and hyperthyroidism. The failure to treat sick people because of one or another blood test that indicates “normal thyroid function,” or the destruction of patients’ healthy thyroid glands because one of the tests indicates hyperthyroidism, isn’t acceptable just because it’s the professional standard, and is enforced by benighted state licensing boards. Toward the end of the twentieth century, there has been considerable discussion of “evidence-based medicine.” Good judgment requires good information, but there are forces that would over-rule individual judgment as to whether published information is applicable to certain patients. In an atmosphere that sanctions prescribing estrogen or insulin without evidence of an estrogen deficiency or insulin deficiency, but that penalizes practitioners who prescribe thyroid to correct symptoms, the published “evidence” is necessarily heavily biased. In this context, “meta-analysis” becomes a tool of authoritarianism, replacing the use of judgment with the improper use of statistical analysis. Unless someone can demonstrate the scientific invalidity of the methods used to diagnose hypothyroidism up to 1945, then they constitute the best present evidence for evaluating hypothyroidism, because all of the blood tests that have been used since 1950 have been.shown to be, at best, very crude and conceptually inappropriate methods. Thomas H. McGavack’s 1951 book, The Thyroid, was representative of the earlier approach to the study of thyroid physiology. Familiarity with the different effects of abnormal thyroid function under different conditions, at different ages, and the effects of gender, were standard parts of medical education that had disappeared by the end of the century. Arthritis, irregularities of growth, wasting, obesity, a variety of abnormalities of the hair and skin, carotenemia, amenorrhea, tendency to miscarry, infertility in males and females, insomnia or somnolence, emphysema, various heart diseases, psychosis, dementia, poor memory, anxiety, cold extremities, anemia, and many other problems were known reasons to suspect hypothyroidism. If the physician didn’t have a device for measuring oxygen consumption, estimated calorie intake could provide supporting evidence. The Achilles’ tendon reflex was another simple objective measurement with a very strong correlation to the basal metabolic rate. Skin electrical resistance, or whole body impedance wasn’t widely accepted, though it had considerable scientific validity. A therapeutic trial was the final test of the validity of the diagnosis: If the patient’s symptoms disappeared as his temperature and pulse rate and food intake were normalized, the diagnostic hypothesis was confirmed. It was common to begin therapy with one or two grains of thyroid, and to adjust the dose according to the patient’s response. Whatever objective indicator was used, whether it was basal metabolic rate, or serum cholesterol, or core temperature, or reflex relaxation rate, a simple chart would graphically indicate the rate of recovery toward normal health. http://raypeat.com/articles/articles/thyroid.shtml REFERENCES McGavack, Thomas Hodge.: The thyroid,: St. Louis, Mosby, 1951. 646 p. ill.Several chapters contributed by various authors. Call Numbers WK200 M145t 1951 (Rare Book). Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. Pardridge WM. Endocrinology 1987 Apr;120(4):1590-6. Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger A.G. J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM. Previous studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used Endocrinology 113(1), 391-8, 1983, Stimulation of sugar transport in cultured heart cells by triiodothyronine (T2) covalently bound to red blood cells and by T3 in the presence of serum, Dickstein Y, Schwartz H, Gross J, Gordon A. Endocrinology 1987 Sep; 121(3): 1185-91. 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Watanabe S, Tani T, Watanabe S, Seno M Kanagawa. D Novitzky, H Fontanet, M Snyder, N Coblio, D Smith, V Parsonnet, Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery, Cardiology, 1996, Vol 87, Iss 6, pp 509-515. Biochim Biophys Acta 1997. Jan 16;1318(1-2):173-83 Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones. Starkov AA, Simonyan RA, Dedukhova VI, Mansurova SE, Palamarchuk LA, Skulachev VP Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of triiodothyronine in cardiac transplantation. Novitzky D. Rev Med Chil 1996 Oct;124(10):1248-50. [Severe cardiac failure as complication of primary hypothyroidism]. Novik V, Cardenas IE, Gonzalez R, Pena M, Lopez Moreno JM. Cardiology 1996 Nov-Dec;87(6):509-15. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V Curr Opin Cardiol 1996 Nov;11(6):603-9. The use of thyroid hormone in cardiac surgery. Dyke C N Koibuchi, S Matsuzaki, K Ichimura, H Ohtake, S Yamaoka. Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar cortex of the perinatal hypothyroid rat. Endocrinology, 1996, Vol 137, Iss 11, pp 5096-5108. Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. [Article in Russian] Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A. The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Am J Physiol 1997 Sep;273(3 Pt 1):C859-67. Cytoplasmic codiffusion of fatty acids is not specific for fatty acid binding protein. Luxon BA, Milliano MT [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA, Biokhimiia 1985 Nov;50(11):1926-32. The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed. [The nature of thyroid hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Sep;49(9):1478-85. T4- and T3-binding proteins of rat liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific antibodies against TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and matrix. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Aug;49(8):1350-6.. The in vivo translocation of thyroxine- binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Endocrinology 1987 Apr;120(4):1590-6 Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger AG. Gen Comp Endocrinol 1996 Aug;103(2):200-8 Characteristics of the uptake of 3,5,3'-triiodo-L-thyronine and L-thyroxine into red blood cells of rainbow trout (Oncorhynchus mykiss). McLeese JM, Eales JG. Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R. Biochem J 1982 Oct 15;208(1):27-34. Evidence that the uptake of tri-iodo-L-thyronine by human erythrocytes is carrier-mediated but not energy-dependent. Docter R, Krenning EP, Bos G, Fekkes DF, Hennemann G. J Clin Endocrinol Metab 1990 Dec;71(6):1589-95. Transport of thyroid hormones by human erythrocytes: kinetic characterization in adults and newborns. Osty J, Valensi P, Samson M, Francon J, Blondeau JP. J Endocrinol Invest 1999 Apr;22(4):257-61. Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat. Moreau X, Lejeune PJ, Jeanningros R. © Ray Peat 2006. www.RayPeat.com

Written by Agata Bielecka-Dabrowa , Dimitri P Mikhailidis , Jacek Rysz  & Maciej Banach   Thyroid Research volume 2 , Article number: 4 (2009) Abstract Atrial fibrillation (AF) is a complex condition with several possible contributing factors. The rapid and irregular heartbeat produced by AF increases the risk of blood clot formation inside the heart. These clots may eventually become dislodged, causing embolism, stroke and other disorders. AF occurs in up to 15% of patients with hyperthyroidism compared to 4% of people in the general population and is more common in men and in patients with triiodothyronine (T3) toxicosis. The incidence of AF increases with advancing age. Also, subclinical hyperthyroidism is a risk factor associated with a 3-fold increase in development of AF. Thyrotoxicosis exerts marked influences on electrical impulse generation (chronotropic effect) and conduction (dromotropic effect). Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk, including elevation of left atrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation, ischemia resulting from increased resting heart rate, and increased atrial eopic activity. Reentry has been postulated as one of the main mechanisms leading to AF. AF is more likely if effective refractory periods are short and conduction is slow. Hyperthyroidism is associated with shortening of action potential duration which may also contribute to AF. Introduction Atrial fibrillation (AF) is a common dysrrhythmia representing an independent risk factor for cardiovascular events [ 1 ]. The rapid and irregular heartbeat produced by AF increases the risk of blood clot formation inside the heart. These clots may eventually become dislodged, causing embolism, stroke and other disorders [ 1 , 2 ]. AF is a complex disease with several possible mechanisms. Studies indicate that arrhythmogenic foci within the thoracic veins can be AF initiators [ 2 ]. Once initiated, AF alters atrial electrical and structural properties in a way that promotes its own maintenance; this increases the risk of recurrence and may alter the response to antiarrhythmic drugs [ 2 , 3 ]. AF may occur in patients with a variety of cardiovascular or chronic diseases as well as in normal subjects. It is the most common cardiac complication of hyperthyroidism [ 3 ]. AF in thyrotoxicosis is associated with significant mortality and morbidity resulting from embolic events [ 3 ]. The risk factors for AF in patients with hyperthyroidism (age, male sex, ischemic heart disease, congestive heart failure and valvular heart disease) are similar to those in the general population [ 4 ]. AF occurs in up to 15% of patients with hyperthyroidism [ 5 ] compared with 4% incidence in the general population [ 6 ] and is more common in men and in patients with triiodothyronine (T3) toxicosis [ 3 ]. Also, subclinical hyperthyroidism is a risk factor that is associated with a 3-fold increase in risk of developing AF [ 5 ]. AF incidence increases with advancing age. Although it is rare in patients under 40 years of age, 25% to 40% of hyperthyroid individuals over the age of 60 experience AF, possibly reflecting an age-related reduction in threshold for acquiring this arrhythmia. Of hyperthyroid patients older than 60 years, 25% had AF compared with 5% prevalence in patients younger than 60 years [ 7 ]. Patients with toxic nodular goiter also showed, because of their age, an increased prevalence of AF versus younger patients with Graves' disease (43% vs 10%, respectively). Also, analysis of rhythm disorders in 219 patients with hyperthyroidism [ 8 ] showed an age-dependent distribution of AF and sinus node dysfunctions. In a large study [ 9 ] of patients with new-onset AF, less than 1% of AF incidence was caused by overt hyperthyroidism. Therefore, although serum thyroid-stimulating hormone (TSH) is measured in all patients with new-onset AF to rule out thyroid disease, this association is uncommon in the absence of additional symptoms and signs of hyperthyroidism. Treatment of hyperthyroidism results in conversion to sinus rhythm in up to two-thirds of patients. In a prospective trial, the arrhythmia profile was analyzed in hyperthyroid patients, before, during, and after antithyroid therapy [ 10 ]. The number of patients with atrial premature complexes was elevated compared with controls (88 vs 30%) and decreased markedly after treatment. As with other causes of AF, the main determinant of reversion seems to be the duration of AF [ 11 ]. Patients who had been in AF for more than 1 year and those who were in advanced age were likely to need intervention in the long run, probably reflecting the coexistence of ischaemic heart disease in these hyperthyroid patients with AF [ 12 ]. No association of subclinical hypothyroidism with AF has been found [ 5 , 13 – 15 ]. The 'hypothalamic -pituitary -thyroid axis' Thyroxine (T4) and triiodothyronine (T3) are tyrosine-based hormones produced by the thyroid gland. The major form of thyroid hormone in the blood is thyroxine (T4). The ratio of T4 to T3 in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 form (3 to 4 times more potent than T4) by deiodinases. TSH stimulates the thyroid gland to secrete the thyroid hormones. TSH production is controlled by thyrotropin releasing hormone (TRH), which is synthesised in the hypothalamus and transported to the anterior pituitary gland via the superior hypophyseal artery, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release. The levels of T3 and T4 in the blood have a feedback effect on the pituitary release of TSH. When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop. Subclinical hyperthyroidism as a risk for AF Subclinical hyperthyroidism is defined as low serum thyrotropin concentration in an asymptomatic patient with normal serum T3 and T4 concentration [ 16 ]. The prevalence among adults is up to 12% and increases with age [ 16 – 18 ]. Subclinical hyperthyroidism can occur as a result of thyroid pathology such as Graves' disease, multinodular goiter, or autonomous toxic nodules or may be exogenous due to thyroxine therapy [ 18 ]. Subclinical hyperthyroidism may be a consequence of L-thyroxine (L-T4) therapy [ 19 ]. The abnormalities found in patients with subclinical hyperthyroidism are increased heart rate and prevalence of supraventricular arrhythmias and enhanced left ventricular mass (LVM) due to concentric remodeling [ 19 ]. The increase in LVM is associated with slightly enhanced systolic function and almost always with impaired diastolic function due to slowed myocardial relaxation [ 19 – 23 ]. It rarely corresponds to actual left ventricle hypertrophy and is related to the duration of subclinical hyperthyroidism rather than to circulating thyroid hormone levels. It is assumed that these changes develop in response to a chronic hemodynamic overload due to the mild hyperkinetic cardiovascular state [ 24 ]. It is reported that a low serum thyrotropin concentration in an asymptomatic person with normal serum thyroid hormone concentrations can be an independent risk factor for developing AF [ 24 , 25 ]. A retrospective cross-sectional study [ 14 ] compared AF prevalence in 1338 subjects with overt or subclinical hyperthyroidism due to autonomous thyroid nodules or Graves disease with AF prevalence in a control group of 22300 subjects admitted to a hospital. The prevalence of AF was 13.8% in patients with overt hyperthyroidism, 12.7% in those with subclinical hyperthyroidism, and 2.3% in euthyroid controls. The relative risk (RR) of AF in those with subclinical hyperthyroidism was 5.2 (95% CI, 2.1–8.7) compared with controls. Thus, a low serum TSH concentration is associated with a more than 5-fold higher likelihood for the presence of AF. There was no significant difference between the risk of AF in patients with subclinical and overt hyperthyroidism [ 14 ]. In another study [ 5 ] in patients older than 60 years, subjects with low thyrotropin (<0.1 mU/L) had a 28% incidence of AF compared with 11% in normal subjects. The patients with slightly lower serum thyrotropin concentration (0.1 to 0.4 mU/L) also had a higher risk of AF than those with a normal thyrotropin concentration (RR 1.6; p = 0.05). There was no significant difference in AF occurrence between overt and subclinical hyperthyroidism [ 5 ]. Similar findings have been reported by Cappola et al. [ 13 ] investigating incident AF in 3233 US community-dwelling subjects 65 years or older. After exclusion of those with preexisting AF, those with subclinical hyperthyroidism (1.6% of the cohort) had a greater incidence of AF compared with those with normal thyroid function over a period of 12 years [adjusted hazards ratio (HR), 1.98; 95% CI, 1.29–3.03]. In the study of Kwon et al. [ 25 ] the significance of serum TSH in the euthyroid patient with AF whose serum level of T3, T4, free T4 (fT4), and were absolutely within normal range was assessed. The cutoff serum TSH value that distinguished between paroxysmal and chronic AF was 1.568 U/mL (76% predictive power). There was a significantly lower serum TSH in paroxysmal AF in all age groups (p < 0.05). The authors suggest that serum TSH below the serum concentration of 1.5 U/mL can be a risk factor for developing AF. Overt hyperthyroidism and AF risk In a large study including more than 23000 persons, AF was present in 513 subjects (2.3%) in the group with normal values for serum TSH, and in 78 (12.7%) and 100 (13.8%) in the groups with subclinical and overt hyperthyroidism, respectively [ 14 ]. In the study of Gammage et al. [ 26 ], serum fT4 was an independent predictor of the presence of AF in the cohort as a whole, and this association was sustained after exclusion of those with overt thyroid dysfunction. Furthermore, when the analysis was further restricted to those classified as euthyroid (with normal serum TSH concentration), the relationship between serum fT4 and AF was still evident. In the Rotterdam Study [ 27 ] patients with high normal serum fT4 concentrations also had a higher risk of AF. The multivariate adjusted level of fT4 showed a graded association with the risk of AF (HR, 1.62; 95% CI, 0.84–3.14, highest versus lowest quartile; p for trend, 0.06). Effects of thyroid hormones on the cardiovascular system Overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias [ 28 ]. Thyroid hormones may exert both genomic and nongenomic effects on cardiac myocytes [ 28 ]. The genomic effects of thyroid hormones are mediated by transcriptional activation or repression of specific target genes that encode both structural and functional proteins [ 29 ]. Triiodothyronine (T3) is the biologically active thyroid hormone that gets into the cardiomyocyte through specific transport proteins located within the cell membrane, and which then interacts with specific transcriptional activators (nuclear receptor α-1) or repressors (nuclear receptor α-2) [ 30 ]. Occupancy of these receptors by T3, in combination with recruited cofactors, allows the thyroid hormone-receptor complex to bind (nuclear receptor α-1) or release (nuclear receptor α-2) specific sequences of DNA (thyroid-responsive elements) that, in turn, by acting as cis - or trans -regulators, modify the rate of transcription of specific target genes [ 28 , 31 ]. Severely hyperthyroid patients can show signs of congestive heart failure in the absence of prior cardiac pathology [ 32 ]. Cardiac manifestations in hyperthyroid patients can be the result of thyrotoxicosis itself, underlying heart disease that decompensates due to hyperthyroidism-induced increased demand on the heart, or increased occurrence of specific cardiac abnormalities [ 32 ]. Hyperthyroid patients frequently complain of dyspnea on exertion even in the absence of cardiac failure [ 33 ]. Because hyperthyroidism leads to a weakening of skeletal and intercostal muscles, dyspnea may be related more to a weakness of respiratory muscles than to cardiac abnormalities themselves [ 33 – 38 ]. Several lines of evidence suggest that some abnormalities of cardiac function in patients with thyroid dysfunction directly reflect the effects of thyroid hormones on calcium-activated ATPase and phospholamban, which are involved primarily in the regulation of systodiastolic calcium concentrations in cardiomyocytes [ 34 ]. Sarcoplasmic reticulum calcium-activated ATPase is responsible for the rate of calcium reuptake into the lumen of the sarcoplasmic reticulum during diastole that, in turn, is a major determinant of the velocity of myocardial relaxation after contraction [ 29 , 34 ]. It has been extensively demonstrated that thyroid hormone upregulates expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulates expression of phospholamban, thereby enhancing myocardial relaxation [ 29 , 34 ]. The improved calcium reuptake during diastole may favorably affect myocardial contractility [ 34 ]. Some evidence indicates that thyroid hormones promote the acute phosphorylation of phospholamban and that this action attenuates the inhibitory effect of phospholamban on sarcoplasmic reticulum calcium-activated ATPase [ 35 ]. Interestingly, the fact that this process is mediated at least in part by the activation of intracellular kinase pathways involved in signal transduction of adrenaline [ 35 ] may help to explain functional analogies between the cardiovascular effects of thyroid hormone and those promoted by the adrenergic system [ 36 ]. The circadian rhythm of heart rate is maintained in thyrotoxicosis, although heart rate variability is significantly increased, supporting the view that normal adrenergic responsiveness persists in thyrotoxicosis [ 37 ]. Electrophysiological mechanism of AF in hyperthyroidism Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk, including elevation of left atrial pressure secondary to increased LVM and impaired ventricular relaxation [ 28 ], ischemia resulting from raised resting heart rate, and increased atrial ectopic activity [ 39 ]. Studies using an isolated heart model found that hearts from animals with experimental thyrotoxicosis show increased heart rates and shorter mean effective refractory periods than hearts from euthyroid animals [ 37 ]. In patients with hyperthyroidism increased heart rate and a decreased turbulence slope (TS) (TS quantifies the rate of sinus slowing that follows the sinus tachycardia) consistent with decreased vagal tone were observed [ 40 ]. Hyperthyroidism is associated with an increased supraventricular ectopic activity in patients with normal hearts [ 40 ]. Wustmann et al. [ 40 ] assessed the activity of abnormal supraventricular electrical depolarizations at baseline and follow-up after normalization of serum TSH levels. The abnormal premature supraventricular depolarization, the number of episodes of supraventricular tachycardia and nonsustained supraventricular tachycardia decreased significantly (p = 0.003, p < 0.0001, p = 0.01) after normalization of serum thyrotropin levels. The activation of arrhythmogenic foci by elevated thyroid hormones may be an important causal link between hyperthyroidism and AF. Heart rate effects are mediated by T3-based increases in systolic depolarization and diastolic repolarization and decrease in the action potential duration and the refraction period of the atrial myocardium, as well as the atrial/ventricular nodal refraction period. T3 induces electrophysiological changes partly due to its effects on sodium pump density and enhancement of Na+ and K+ permeability [ 41 ]. Expression of the L-type calcium channel 1D, which also serves as an important pacemaker function, is also increased by T3. In vitro studies found that T3 decreases the duration of the repolarization phase of the membrane action potential and increases the rate of the diastolic repolarization and therefore the rate of contraction [ 42 – 44 ]. Reentry has been postulated as one of the main mechanisms leading to AF [ 45 – 47 ]. Multicircuit wave fronts that are generated in the atrium could disturb normal sinus rhythm and set up a fibrillatory rhythm [ 45 – 47 ]. According to wavelength concepts, AF is more likely if effective refractory periods are short and conduction is slow [ 47 ]. Hyperthyroidism is associated with shortening of action potential duration [ 47 ]. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry [ 46 , 47 ]. It has been reported that the properties of electrophysiological repolarization are not homogeneous within the 2 atria. Li et al. [ 48 ] determined that the higher density of the rapid delayed rectifier current ( I Kr) in left atrial myocytes contributed to the shorter effective refractory period and APD in canine left atrium. In several studies, changes have been observed in the expression of various ion channel mRNAs in both atria [ 49 , 50 ] and ventricles [ 49 , 51 , 52 ] under hyperthyroid conditions. Watanabe et al. [ 50 ] revealed a remarkable increase in the ultrarapid delayed rectifier potassium currents in hyperthyroid compared with euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid compared to euthyroid myocytes. T3 increased the outward currents and decreased the inward currents, resulting in shortened APD. Between the atrium and ventricle of the adult rat heart, the responses of gene expression of voltage-gated potassium channels to T3 were different and the variability of responses may explain cardiac manifestations of hyperthyroidism [ 49 ]. Hu et al. [ 53 ] assessed the electrophysiological changes that occur in left and right atria with hyperthyroidism, the patch-clamp technique was used to compare APD and whole cell currents in myocytes from left and right atria in both control and hyperthyroid mice. The RNAse protection assay and Western blotting were used to evaluate the mRNA and protein levels of α-subunits constituting the corresponding ion channel pore in the atrium. In hyperthyroid mice shortened APD and increased delayed rectifier currents (both the ultra-rapid delayed rectifier K+ conductance - I Kur and the sustained delayed rectifier K+ conductance - I ss) in atrial myocytes were observed. Messenger RNA and protein expression levels of the main potential pore-forming subunits for these 2 currents, Kv1.5 and Kv2.1, were also higher in both atria in this group. It is likely that increased Kv1.5 and Kv2.1 expression reflects increased channel synthesis and at least partially contributes to the higher density of I Kur and I ss obtained under hyperthyroid conditions. The association between alteration of Kv1.5 protein but not Kv2.1 expression and mRNA level was observed in hyperthyroid atria. This suggests that thyroid hormones may regulate Kv2.1 expression at a posttranscriptional level. The influence of hyperthyroidism on APD and delayed rectifier K+ currents was more prominent in right than in left atrium, which minimized the interatrial APD difference. Several factors such as differential pressure stress force, autonomic nerve innervation, or different transcriptional factor distribution between the 2 atria may play a role in this process. The overall shortening of action potential duration in hyperthyroid atria, which is reflective of a shorter effective refractory period, would facilitate the occurrence of reentry. Contrary to the normal interatrial APD difference that is important for synchronizing contraction of both atria (due to the physiological origination of sinus rhythm on the right side), the diminished interatrial APD difference may enhance the spreading of ectopic activity originating mostly from left atrium to the whole atria. Therefore, it is possible that the diminished interatrial APD would facilitate the generalization of irregular activities in a hyperthyroid state and provide the substrate for atrial arrhythmias such as AF [ 53 ]. Pulmonary veins are known to initiate paroxysmal AF [ 54 ]. Increased automaticity may also play a role in the arrhythmogenesis in hyperthyroid pulmonary veins [ 54 ]. Research using rabbit pulmonary vein cardiomyocytes has shown that thyroid hormones decrease the APD in pulmonary vein cardiomyocytes which can decrease the refractory interval and facilitate the genesis of reentrant circuits [ 54 , 55 ]. Incubation with thyroid hormones also increased spontaneous activity in pulmonary vein cardiomyocytes similar to its effect on sinoatrial node cells. Previous studies in humans or in isolated canine pulmonary vein tissues also have demonstrated that triggered activities may underlie the arrhythmogenic activity of pulmonary veins [ 55 , 56 ]. Thyroid hormones induced the occurrence of delayed after-depolarization (DAD) in beating and non-beating pulmonary vein cardiomyocytes. Transient inward currents have been suggested to play an important role in the genesis of DAD [ 57 , 58 ]. Tseng and Wit [ 57 ] showed that transient inward currents may play a role in the triggered activity of atrial cells in the coronary sinus. In the studies by Chen et al. [ 54 – 56 ] both the beating and non-beating hyperthyroid pulmonary vein cardiomyocytes had greater transient inward currents after being incubated with thyroid hormones, which may underlie the high incidence of DAD in these cells. In the beating cardiomyocytes, the incidence of early depolarization (EAD), defined as the generation of oscillatory potentials at depolarized levels, was also increased after incubation with thyroid hormones [ 54 – 56 ]. These findings suggest that thyroid hormones may induce the occurrence of paroxysmal AF through the increase of triggered activity in pulmonary veins. Thyroid hormones have little effects on the triggered activity of atrial cells, which suggests that these cells have different responses to thyroid hormone. Is it necessary to screen for thyroid function? Regarding the high incidence of AF in older patients with thyrotoxicosis, it is important to detect thyroid dysfunction in subjects over 60 year of age. Once euthyroidism is restored, all patients who revert spontaneously to sinus rhythm (~60%) do so within 4 months of becoming euthyroid [ 59 ]. The finding that subclinical hyperthyroidism detected as a result of screening is associated with AF contributes to the debate about the value of screening at-risk populations. This debate needs to be informed by evidence from trials investigating whether treatment prevents or reverses AF [ 26 ]. Screening thyroid function tests to exclude occult hyperthyroidism as the cause of AF should include total or free T3 and T4 and high sensitivity TSH measurements. Triiodothyronine concentration may be within the reference range in patients who are hyperthyroid and have AF [ 59 ]. The measurement of T4 alone can be also unsatisfactory, especially in patients with thyrotoxicosis, particularly if they have been treated for hyperthyroidism, with a nodular goitre or an autonomous thyroid nodule [ 60 ]. The TSH-producing cells of the anterior pituitary are sensitive to minor changes in circulating thyroid hormones and absent or subnormal TSH concentrations may be found in hyperthyroid patients in whom the T3 and T4 concentrations are higher than normal for the individual but within or at the upper end of the accepted reference range. An electrocardiogram may be helpful in identifying hyperthyroid subjects at risk for developing AF. Maximum P wave duration and P wave dispersion were higher in both subclinical and overt hyperthyroidism. P maximum and P wave dispersion were significant predictors of paroxysmal AF [ 60 – 62 ]. Conclusions Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk and this association is well documented in the literature. It is especially important to detect thyroid dysfunction in all subjects over 60 year of age, as once euthyroidism is restored all patients who revert spontaneously to sinus rhythm do so within 4 months of becoming euthyroid. The finding that subclinical hyperthyroidism detected as a result of screening is associated with AF contributes to the debate about the value of screening at-risk populations. This debate still needs to be informed by evidence from trials investigating whether treatment prevents or reverses AF [ 59 , 60 ]. 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Written by Dr. John C. Lowe on his platform Thyroid Science, with questions and answers. June 20, 2010 Question: I am a general practitioner in the UK. Many of my patients have told me that they recovered from their hypothyroid symptoms after they found a private doctor who treated them with thyroxine despite their normal TSH levels. These patients had been denied thyroxine treatment by doctors within the National Health Service because of their normal TSH levels. So many patients have told me this that I have developed reservations about ruling out hypothyroidism and the need for thyroxine therapy based on a normal TSH test. Many more of my patients with normal TSH levels ask me to prescribe thyroxine or Armour Thyroid. I am hesitant to comply because of the Royal College of Physicians' statement about adverse effects from unnecessary thyroid hormone therapy. May I have your point of view on the potential for adverse effects from thyroxine treatment when patients do not actually need it? Dr. Lowe: I'm familiar with the statement you refer to by the Royal College of Physicians. Specifically it is: ". . . some patients are inappropriately diagnosed as being hypothyroid (often outside the NHS) and are started on thyroxine or other thyroid hormones which will not only cause them possible harm . . ." (Italics and bold mine.) Like too many other statements or implications by the Royal College of Physicians, when applied to the general population, this one is patently false. Unless you're a geriatric specialist whose patients are among the most fragile of human beings, even if they don’t need supplemental thyroid hormone, a trial of thyroid hormone therapy is harmless. If the hormone doesn’t help them, you can wean them off it and then have them stop it altogether. No harm done! Proof of this is in the history of FDA-guided studies of the potency and stability of T4. To test T4 for potency and stability, researchers— using FDA test guidance! —have traditionally used volunteers who were "euthyroid," meaning, of course, that they subjects had normal thyroid function test results. Moreover, FDA test guidance has allowed researchers to use euthyroid volunteers to test higher-than-physiological (supraphysiologic) doses of T4.[1,p.109] I ask the Royal College of Physicians: If it were likely to harm euthyroid volunteers, why would FDA-test guidance allow researchers to use them for the testing? And why would institutional review boards approve the studies as not potentially harmful to the volunteers? The answer is simple, of course: A trial of thyroid hormone therapy—even for people with perfectly normal thyroid function—is harmless , even when they use supraphysiologic doses. Only recently have researchers suggested that rather than testing euthyroid volunteers, they would best use thyroidectomized patients. But the researchers' reason for this suggestion has nothing whatever to do with any harm ever done to euthyroid volunteers in the studies. The testing hasn't harmed the euthyroid volunteers, nor will a trial of thyroid hormone therapy harm practically any of your euthyroid patients except possibly the most severely fragile of them. But, then, a cup of coffee is just as likely to harm those fragile folks. I just don't understand something: How does the Royal College of Physicians (as with this particular issue) and the British Thyroid Association make scientifically false statements and stand by them in the face of proof that they are false, yet receive no official reprimands from regulatory authorities in the UK? To me, their false statements are an affront to the noble tradition of science, and the organizations sticking by their false statements in the face of refuting evidence reduces the statements to examples of pseudoscience. At any rate, I hope this reply is helpful to you in providing your patients with harmless trials of thyroid hormone therapy, whether they truly need it or not. References 1. Royal College of Physicians. The diagnosis and management of primary hypothyroidism . 2008. 2. Eisenberg, M. and DiStefano, III, J.J.: TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4 Bioequivalence . Thyroid , 19(2):103-110, 2009. (This Q&A was published simultaneously at drlowe.com ) June 12, 2010 Question: I have a hypothesis paper that I’m considering submitting to Thyroid Science . I’m hesitant, however, because there may be advantages to publishing in major medical journals, such as the Journal of the American Medical Association . Of course, I may have a harder time getting my paper accepted because of competition. What are your thoughts for people who are new to submitting papers to journals? Can I submit my paper both to Thyroid Science and another journal and go with which ever journal accept it? Dr. Lowe: Many people have asked us this same question. Of course, we would like a chance to publish your paper if our reviewers believe it has merit in the field of thyroidology. However, if your paper may contribute to changing the current “T4 replacement paradigm” for hypothyroidism, we really don't care which journal first publishes it, as long as you get it published. To some, that policy may seem self-sabotaging to Thyroid Science, but it really isn't. If we feel that a paper published elsewhere is important enough, we'll ask the author(s) to write a summary of the paper for our journal, possibly further articulating the thesis and providing more supporting evidence. And if the author won’t cooperate, we may compose a paper based on the author(s)' that provides the important information for our readers. In deciding where to submit your paper, you might keep in mind a few points I wrote to another potential author this morning. What I wrote to him is essentially the following. Long ago, when I was being educated in research psychology (I think Galileo sat two rows in front of me), I took courses that dealt with the ethics of scientific conduct. We were taught that it's unethical to publish exactly the same paper in more than one journal, even if years have passed since the first publication. That policy is an old one, and it still applies. Because of this, you should submit your paper only to one journal at a time. If the first journal rejects your paper, then, and only then, submit it to the next one. If you want to spread your hypothesis wider than one journal would allow, you can easily do that. First, publish your paper in one journal, and write as many otherpapers as you want for other journals. This is perfectly ethical as long as your other versions of your paper are indeed other versions; that is, in subsequent papers, you should express your hypothesis exactly as it was originally published, but in different terms . Expressing the same thoughts in different terms is ethical. In my view, in fact, if you feel that your hypothesis can lead to the relief of suffering of human beings, you have a humanitarian responsibility to publish it as many times as needed to accomplish that worthy end. If you can get your paper accepted by a major traditional print journal, you'll have some important advantages. For example, you're likely to have more prestige in the eyes of the typical practicing conventional clinician, and your paper will be included in the traditional major indexing systems, such as Medline. On the other hand, the print journal may fail to publish your paper in an open-access electronic version of the journal. If so, only those who subscribe to the print version of the journal are likely to read your full paper. As time passes, the only part of your paper that most interested people will have access to will be the abstract that is online. They can access your abstract through most search engines, such as Google and Yahoo. Otherwise, if anyone is interested enough in arrange to get a copy of your full paper, he or she will have one of two options: First, he or she can buy a copy online from the closed-access journal. This can be expensive, and it can be prohibitive if one does a great deal of journal research. Second, he or she can travel to a medical library, track down your paper in a bound volume of all the papers published in that journal during the year, and photocopy it. This option is inconvenient for most people. This may account for me seeing in recent years fewer and fewer people in medical libraries copying journal papers. Another downside of traditional print journals is something that frustrated many of us who used to publish in traditional print journals: the “publication lag.” I know of some journals that had a lag of two years. This meant that by the time one’s paper was published, it was more history than news. Because of the publication lag, I encourage you talk or write to an editor of the journal you decide to submit to. As whether in addition to publishing a print version, the journal will also rapidly publish an electronic version online. Another important issue is whether the journal is available only to subscribers ("closed-access") or is "open-access." Open-access means that most publications in the journal are free to read without a subscription. Steadily more open-access journals are being published, and they are impacting traditional print journals. When I've inquired, medical librarians, who work where traditional print journals are stored, have told me, “open-access journals are killing us.” One advantage of electronic publishing, especially in open-access journals such as Thyroid Science , is that we have virtually no publication lag. We publish papers are rapidly compared to print journals. In addition, with open-access journals, anyone in the world with access to the Internet can find and read your paper using Google, Yahoo, or most any other search engines. One doesn't even need to use Medline, PubMed, or any of the other traditional indexing system. In fact, I believe these systems are on the verge of being obsolete. Most search engines such as Google also index the papers that formerly were indexed only in the traditional indexing systems. Plus, Internet search engines also indexes publications not included in PubMed. If you publish in another journal for whatever advantage, we fully support you in it. And if you'll send us an advanced copy of your paper, after the other journal publishes it, we may ask you to summarize your hypothesis and elaborate on it in a second paper for Thyroid Science . Best of luck in getting your hypothesis published, wherever you decide to submit your paper. November 24, 2009 Question: My doctor gave me my lab results yesterday. I know what most of the thyroid tests are, but I’ve never heard of one. It is the “prealbumin.” Do you know what this is? My level was 0.20 g/L, and the range is listed as 0.18-to-0.39 g/L. Do you know what this result means? Dr Lowe: We have a newer name for prealbumin, which is “transthyretin.” Transthyretin is a protein that is important to thyroid hormone regulation of the brain. The protein transports thyroid hormone across the blood-brain barrier; that is, from the blood outside the brain to the blood inside brain. Transthyretin that ransports thyroid hormone in the blood is produced in the liver, but transthyretin that transports thyroid hormone across the blood brain barrier is produced in a structure called the “choroid plexus” at the base of the brain. When I say that the protein transports thyroid hormone across the blood-brain barrier, I mean that it transports both T4 and T3. This is important to understand. The reason is that many clinicians mistakenly think that transthyretin transports only T4 into the brain. Based on this mistaken belief, these clinicians also mistakenly believe that normal brain function depends on patients including T4 in their thyroid hormone therapy. This, however, is patently false. (Elsewhere, I extensively documented that transthyretin transports both T4 and T3 into the brain. I published one article in 2005 and the second in 200 6.) You wrote that your transthyretin level was 0.20 g/L (20 mg/dL). With a range of 0.18-to-0.39 g/L (18-to-39 mg/dL), your level is very low; it’s in the lower 4th of the range. Some diagnosticians would say this level means you’re not producing an optimal amount of transthyretin; others would say that you’re producing plenty. I don’t think we have enough studies to tell us which of those diagnosticians are right and wrong. What we can tell from your level is that you’re producing the protein and your most likely getting thyroid hormone into your brain. We don’t have tests commercially available that measure the amount of thyroid hormone that is bound to one’s transthyretin. That piece of information would be valuable. The reason is that dioxins and PCBs can displace thyroid hormone from the protein. As a result, these chemical contaminants can ride into the brain on the protein. The more of the contaminants that ride the protein into the brain, the less T4 and T3 are likely to reach brain cells. Once inside the brain, dioxins and PCBs bind to T3 receptors on genes. The binding alters the pattern of codes that the genes send out to the work part of the cell for the production of proteins. I believe this phenomenon is responsible for some of the cognitive and mood problems of people contaminated with dioxins and PCBs, which toxicologists have told me is each of us. (I heavily documented the thyroid-disrupting effects of these pollutants in the “Environmental Contaminants” section in Chapter 2.4, “Thyroid Hormone Deficiency,” of The Metabolic Treatment of Fibromyalgia [available in the publisher's E-Chapter section ].) I assume that you wrote to me about your transthyretin level from concern about your thyroid hormone status. However, some clinicians order the test to learn whether a patient is ingesting enough protein. Transthyretin is a “glycoprotein,” which means it is a carbohydrate combined with a protein. Of all the proteins in the blood, it’s transthyretin that is most useful in telling whether a person has a protein deficiency. The half life of the protein is about two days, so it’s level in the blood changes quickly when someone markedly decreases or increases protein intake, digestion, and/or absorption. You didn’t say whether you ate little to no protein for several days before your blood was drawn to measure your transthyretin. If you ate little to none, that might account for your low-range transthyretin level. If that is the case, you should talk with your clinician about measuring your transthyretin level again after you eat 50-to-75 grams of protein each day for several days. Your tranthyretin level might then be higher. But keep in mind that inflammation and infection can also lower transthyretin level, and severe kidney disease and the use of glucocorticoid (such as prednisone or prednisolone) can raise your level. I hope this is helpful to you. December 8, 2008 Question: I'm so thankful I was told about ThyroidScience.com. I read the article on " Weight Gain and the TSH " and sent it to my three sisters who also suffer from hypothyroidism. I started the Armour Thyroid medication almost two weeks ago and feel so much better than the last 7 years of being on levothyroxine. I know this is a positive start in the right direction for me personally. I have 30 pounds to get rid of that I've gained in the last 7 years after two consecutive pregnancies in 2002 and 2003. Thank you for making this information available to the people (not just doctors) who are pro active about their health. Dr Lowe: Thanks so much for writing about feeling better on Armour Thyroid after gaining thirty pounds of weight while on levothyroxine. If you use a high enough dosage of Armour, I expect that you’ll lose the 30 lbs you gained over the seven years that you used levothyroxine. This is especially likely if you have a wholesome diet and regularly exercise to tolerance. Armour Thyroid , like Nature-Throid and Westhroid , is more effective than levothyroxine at reducing body fat. The reason is that these products contain T3. Some researchers say that T3 has a “lipolytic”—that is, a fat-decomposing—action in fat cells.[3] One way T3 reduces fat in the cells is by inhibiting an enzyme (cyclic-AMP phosphodiesterase) that slows down metabolism shortly after adrenaline and noradrenaline speeds it up.[1][3][8] By blocking this enzyme, T3 sustains the fat-decomposing effect of adrenaline and noradrenaline in fat cells.[1][2][8] Another way T3 reduces fat is by altering gene transcription for several compounds. When T3, acting through the relevant genes, increases fat cells’ production of these compounds, the compounds augment adrenaline’s and noradrenaline’s fat-lowering effect in the cells.[10] In addition to weight loss, you may get another benefit from the T3 in Armour: that is, a reduction of fat that probably accumulated in your arteries[3] while you were on T4 replacement. As Duntas wrote,[11] As Duntas noted in 2002, the composition and transport of blood fats “are seriously disturbed in thyroid diseases.” Among patients with an high TSH and low thyroid hormone levels, cholesterol and LDL are typically high. Even when thyroid hormone levels are within the reference range but the TSH is high, patients on average have a slightly high total cholesterol, high LDL, and low HDL. These patients also have abnormalities of the linings of arteries, inflammation and fat accumulation in the aorta, and they are subject to have myocardial infarctions. They also have increased resistance to blood flow, weaker contractions of the heart muscle, and increase diastolic blood pressure. As Duntas pointed out, thyroid hormone therapy— especially with TSH-suppressive dosages —“usually leads to a considerable improvement in the lipid profile.” T3 reduces fat in artery linings in part by increasing the activity of an enzyme called “lipoprotein lipase.”[4] Low activity of this enzyme leads to high blood fats, which is a risk factor for coronary heart disease.[7] Thyroid hormone increases the activity of the enzyme, and by doing so, it reduces blood fats.[4] Thyroid hormone also lowers LDL cholesterol by increasing the number of LDL receptors on liver cells.[11] In my clinical experience, thyroid hormone therapy (with products that contain T3) is by far more effective than statin drugs in normalizing blood fats. I believe that if patients in general were allowed to use effective thyroid hormone therapy rather than T4 replacement, we could virtually eliminate the market for statin drugs. Then patients would be free from the potential adverse effects of statin drugs, such as chronic muscle pain and other pain syndromes, elevated liver enzymes, peripheral neuropathy, and muscle damage.[9] Please let us know how you progress. I wish you the best for losing the weight you gained while on levothyroxine. References 1. Bégin-Heick, N. and Heick, H.M.: Increased response of adipose tissue of the ob/ob mouse to the action of adrenaline after treatment with thyroxin. Can. J. Physiol. Pharmacol ., 55(6):1320-1329, 1977. 2. Elks, M.L. and Manganiello, V.C.: Effects of thyroid hormone on regulation of lipolysis and adenosine 3',5'-monophosphate metabolism in 3T3-L1 adipocytes. Endocrinology, 117(3):947-953, 1985. 3. Mandel, L.R. and Kuehl, F.A., Jr.: Lipolytic action of 3,3'5-triiodo-L-thyronine, a cyclic AMP phosphodiesterase inhibitor. Biochem. Biophys. Res. Commun. , 28(1):13-18, 1967. 4. Pykälistö, O., Goldberg, A.P., and Brunzell, J.D.: Reversal of decreased human adipose tissue lipoprotein lipase and hypertriglyceridemia after treatment of hypothyroidism. J. Clin. Endocrinol. Metab ., 43(3):591-600, 1976. 5. Beisiegel, U.: Lipoprotein metabolism. Eur. Heart J. , 19 Suppl A:A20-A23, 1998. 6. Otto, W., Taylor, T.G., and York, D.A.: Glycerol release in vitro from adipose tissue of obese (ob/ob) mice treated with thyroid hormones. J. Endocrinol. , 71(1):143-155, 1976. 7. Salter, A.M. and Brindley, D.N.: The biochemistry of lipoproteins. J. Inherit. Metab. Dis ., 11 Suppl 1:4-17, 1988. 8. Wahrenberg, H., Wennlund, A., and Arner P.: Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients. J. Clin. Endocrinol. Metab ., 78(4):898-903, 1994. 9. Brown, W.V.: Safety of statins. Curr. Opin. Lipidol ., 19(6):558-562. 2008. 10. Viguerie, N., Millet, L., Avizou, S., et al.: Regulation of human adipocyte gene expression by thyroid hormone. J. Clin. Endocrinol. Metab. , 2002 Feb;87(2):630-634, 2002. 11. Duntas, L.H.: Thyroid disease and lipids. Thyroid , 12(4):287-293, 2002. November 16, 2008 Question: Has the paper below really been reviewed???? http://www.thyroidscience.com/studies/overbye.2007/overbye.metabolicfailure.fms.lowethesis.pdf I do not question the Lowe thesis, but I believe that a poor paper to support it is in fact harming the cause—especially if the methods used are not backed up with known or accepted methods. Dr Lowe: Thank you for your email and your thoughts. Yes, indeed: Dr. Øverbye’s paper was reviewed. Several of our peer reviewers read the paper, and each strongly recommended that we publish it. As one of the reviewers commented after critiquing Dr. Øverbye’s manuscript, “This paper reports the type of cutting-edge, creative pilot research that we want to encourage.” You suggest that Dr. Øverbye’s paper is "poor" because his methods were "not backed up with known or accepted methods." In conventional medicine, of course, creative research using innovative methods has traditionally been resoundingly discouraged. Recall the dictum, “Be not the first by whom the new is tried, nor the last to lay the old aside.” We at Thyroid Science reject this progress-stifling, herd-mentality orientation. Instead, we encourage originative and progressive clinical methods and research. That orientation is exemplified by Thyroid Science publishing Dr. Øverbye’s paper. As objectionable as this orientation may be to some people within conventional medicine, we steadfastly stand by it, as we believe this orientation is likely to bring help to millions of thyroid patients whom conventional medicine continues to fail. Your assessment of Dr. Øverbye’s study and his paper brings to mind similar notable occurrences. They involved Professor Linus Pauling, a two-time Nobel Prize winner ranked among the ten most fruitful scientists in history. Pauling was also fruitful in his scientific investigations in the field of nutrition. But editors of medical journals often censored him by rejecting or delaying publication of his manuscripts because the contents challenged conventional medical prejudices. (To read his description of the censorship by editors—including the editor of the Journal of the American Medical Association —read his chapter titled “Organized Medicine and the Vitamins” in his book for the public titled How to Live Longer And Feel Better .) By contrast, after some resistance early in his career, chemistry journals accepted Pauling’s thinking and methods that were clearly beyond the boundaries of “the box.” Some editors accepted his manuscripts containing extremely innovative material without sending them to peer reviewers. As one editor noted, peer reviews were impossible in that Pauling had no peers. The chemistry profession got the benefit of Pauling’s imaginative and innovative mind. But censorship of this scientific genius protected from refutation the presumptions and prejudices of the editors, commercial sponsors, and readers of some medical journals. I’m not saying that Dr. Øverbye’s paper is certain to have the gargantuan scientific importance of many of Pauling’s papers (although I'm also not saying it won't). What I am saying is that Thyroid Science will not censor research simply because it involves thoughtful, fresh ideas, and innovative methods. As in Dr. Øverbye’s case, we encourage researchers to use well-established technologies from other fields to make scientific advancements in the field of medicine. He has done this, and admirably so. We appreciate you expressing your opinion and prompting us to explain why our reviewers and editors enthusiastically accepted Dr. Øverbye’s paper for publication. February 23, 2008 Question: Are you aware of the paper by E Tjørve, KMC Tjørve, JO Olsen, R Senum, H Oftebro titled "On commmonness and rarity of thyroid hormone resistance: A discussion based on mechanisms of reduced sensitivity in peripheral tissues" ( Medical Hypotheses , (2007) 69, 913-921 )? In it the authors call for a test for peripheral resistance. Since the standard thyroid function blood tests don't serve this purpose. which of course the standard thyroid function blood tests don't. Maybe the fine-needle aspiration (FNA) technique used by Dr Bo Wikland and his colleagues would fit the bill? Dr Lowe: I have read the E Tjørve paper. I was pleased that Dr. Tjørve and his coauthors mentioned measuring the basal metabolic rate as a method for testing for resistance. I have used the test in my clinical practice for several years and published two studies so far using the method: Report at Medical Science Monitor: http://www.medscimonit.com/abstracted.php?level=4&id_issue=40182 (When you reach the page at Medical Science Monitor , scroll down to the second paper under "Clinical Research". ) Report at Thyroid Science : http://www.thyroidscience.com/studies/lowe.2006/lowe.2nd.rmr.fms.htm Along with Tjorve et al, I believe that the basal or resting metabolic rate measurement is most useful clinically for identifying resistance patients, at least those with peripheral resistance. (Having peripheral resistance, of course, means that a patient's pituitary gland is normally or almost normally responsive to thyroid hormone, but most tissues peripheral to the pituitary are partially resistant.) Dr. Wikland’s FNA identifies patients who have autoimmune thyroiditis despite reference range antithyroid antibody levels. Most of the patients are hypothyroid, which is the reason he and his colleagues term the disorder “subchemical hypothyroidism.” Some of these patients may also have peripheral resistance. But if they improve or recover with doses of thyroid hormone that are lower than supraphysiologic amounts, that would indicate that they are only hypothyroid and not resistant. Most thyroid hormone resistance patients have to use supraphysiologic dosages of T3 to get well. Even T4/T3 products such as Armour usually don't work for them, not unless they use huge dosages, such as 12 grains or more. I have a book published in 1962 written by an endocrinologist—an endocrinologist from the time when many of them practiced clinical medicine rather than the extremist technocratic medicine of most endocrinologists today. In the book, the endocrinologist wrote that some of his “hypothyroid” patients didn't recover until they took as much as 60 grains of desiccated thyroid per day. I assume those patients really had peripheral resistance, as that amount would contain roughly 540 mcg of T3. That's truly a supraphysiologic daily dosage! As I have, Dr. Wikland has found that most hypothyroid patients must suppress their TSH levels before they recover. I don't know the dosages his patients typically use, but if some of them use dosages that are well into the supraphysiologic range, the patients are probably partially resistant to thyroid hormone. I use the following criteria to diagnose peripheral resistance: the patient has before treatment (1) hypothyroid-like symptoms before treatment, (2) reference range TSH and thyroid hormone levels, and (3) an abnormally low resting metabolic rate; and after treatment, he or she (4) recovers from his or her symptoms with a supraphysiologic dosage of plain T3 (5) with no evidence of thyrotoxicosis. There are laboratory methods for testing for resistance. For example, we can use fibroblasts from a patient’s skin. If a supraphysiologic amount of T3 is needed to inhibit the fibroblasts' synthesis and secretion of connective tissue constituents such as fibronectin, then the patient's cells (at least his or her fibroblasts) are resistant to thyroid hormone. I don’t use this particular test for two reasons: first, it isn't available commercially; and second, even if it was, it requires a painful punch biopsy of the skin that I would prefer not to subject patients to. To sum up, Dr. Wikland's FNA can certainly identify patients who are hypothyroid due to autoimmune thyroiditis. However, the procedure would not identify or rule out peripheral resistance to thyroid hormone.

“TSH is Not the Answer,” report Dr. Carol Rowsemitt and Dr. Thomas Najarian: Their explanation and verification Written by Dr. John C. Lowe, MA, DC Recently, we had the privilege of publishing two papers by Carol Rowsemitt, PhD, RN, FNP and Thomas Najarian, MD. These superb papers support views shared by Dr. John Dommisse, Dr. Kenneth Blanchard, and many other advanced, outside-the-box thinkers in modern thyroidology. However, to their credit, Dr. Rowsemitt and Dr. Najarian persuasively elaborate and document that thinking. Rowsemitt and Najarian Papers . One of Rowsemitt and Najarian’s papers is an exemplary example of heavily-substantiated hypothesizing—hypothesizing that has profound practical implications for the health and well-being of hypothyroid patients. The other paper is a laudable description of their clinical protocol based on the hypothesis. I am confident that many of our readers will print, circulate, talk about, and share the papers with other clinicians and patients. Many mainstream clinicians, of course, are at least temporarily still anachronistically stuck in “TSHism.” By this term I mean in part the simplistic belief that a low TSH is synonymous with hyperthyroidism or thyrotoxicosis. And a corollary belief accompanies the first: that is, due to the low TSH, the patient should not use thyroid hormone at all or should reduce his or her dose. Rowsemitt and Najarian convincingly refute both of these beliefs. I doubt that self-asserting promotors of TSHism will respond to Rowsemitt and Najarian’s papers. These authors’ arguments are simply too logical and too grounded in science, as the propositions and citations in their theoretical paper shows. Hopefully, however, those promotors will open-mindedly consider Rowsemitt and Najarians’ way of thinking about weight-burdened thyroid patients and hypothyroid patients in general. Not Anti-TSHism . In doing so, those advocates should not mistake the authors' stance as anti-TSH. Instead, their work is respectful of science and rationality and motivated by humane concern for patients’ well-fare, and their paper clearly puts TSH in proper perspective. Consider a concluding statement of theirs: “We submit these ideas hoping that others will join us in re-evaluating thyroid treatment when maladaptive hypothyroidism occurs during weight loss attempts. Clinicians must use clinical skills and patient-centered concerns in the optimum evaluation and treatment of their patients and not succumb to blindly following an arbitrary system of defined normal lab values in making therapeutic decisions that greatly affect the well-being of their patients.” Lowered Pituitary Set Point . The authors’ papers, I believe, also show a noteworthy drive to be didactically helpful. In that vein, they have cast light on a realistic and fortunate feature of the thyroid system: that when a patient is in a low caloric state, it adapts with sophisticated and complexity to the chronically low intake of calories by slowing metabolism. But, as the authors write, “The patient is often told to get more exercise and that s/he must be eating more calories than realized.” And they show that reducing the patient’s thyroid hormone dose is likely to slow metabolism even further. This misguided treatment approach hinders the adaptive mechanism, reducing calorie expenditure, and perpetuating the patients’ retention of excess weight. Rowsemitt and Najarian write that upon finding a lower in-range TSH, “The provider is likely to conclude that there is nothing wrong with the patient’s thyroid function despite the symptoms.” As they explain, though, the provider is correct in one respect—there is nothing wrong with the patient’s thyroid function. The patient’s lowered TSH is caused by the pituitary’s lowered set point. That lower set point is a life-preserving evolutionary adaptation to low calorie intake. Early humans and even earlier hominids underwent feast/famine cycles that were beyond their control. Modern humans in developed countries have largely eliminated famines. But in times when feast/famine cycles were fairly common, those whose metabolism slowed down during famines had an evolutionary advantage—that is, it enabled them to survive. The survivors, through generations, spawned offspring progressively better able to survive protracted times when food was scarce. They note that humans still have this adaptive advantage despite no shortage of calories for most people today. The adaptation that benefited our ancient ancestors now leads to many hypothyroid patients continuing to suffer from hypothyroid symptoms and excess weight. The reason is that clinicians in general lack an understanding of the adaptive mechanism of a lowered pituitary set point. The resulting lower TSH prompts them to reduce or stop patients thyroid hormone doses, worsening their symptoms and weight gain. Our main problem for many hypothyroid patients today is the abundance of calories that would nullify our need for the adaptive mechanism—had we enough time for evolutionary deletion of the set point phenomenon. I have touched on some of Rowsemitt and Najarian’s points from my enthusiasm for their brilliant and insightful exposition. I am convinced that their papers will do much needed good for hypothyroid patients, especially the weight-laden ones. I strongly encourage patients and clinicians alike to read, print, and disseminate Dr. Rowsemitt and Dr. Najarian’s extraordinary papers.

Written by Kaushik Pandit In the year 1855, Claude Bernard (1813-1878) showed that while the external secretion of the liver was constituted as bile, the internal secretion made blood sugar. It was Bernard who introduced the concept of ‘milieu intérieur’ or internal environment which is kept constant by several interacting, self-regulating mechanisms. Endocrinology was recognized as a new branch of biological science mainly as a result of events which took place between about 1890 and 1905, but ideas and discoveries dating from antiquity contributed to it. As for example, experiments supporting the concept of internal secretions by the testicles were described by Aristotle (4th c. B.C.) but it matured with scientific temper by the experiments of John Hunter (18th c.) and Arnold Berthold (19th c.). The thyroid gland had aroused interest since antiquity. Paracelsus associated goiter with cretinism and noted its frequency in those living in mountainous areas. It was the Dutch anatomist Frederik Ruysch (1638-1731) who enunciated that the thyroid discharged substances into the bloodstream, which was later confirmed by John Simon in 1844. The life sustaining property of thyroid was confirmed by the experiments of Moritz Schiff (1823-1896) in 1856, who showed that in experimental animals, extirpation of thyroid led to their death. The first good clinical description of myxedema was provided by William Withey Gull (1816-1890) in the year 1873, of five adult women presenting with cretinoid condition. They were slow, sluggish, obese and puffy in face. In 1860, Bilroth introduced thyroidectomy as treatment of goiter, and his pupil Emil Theodor Kocher (1841-1917) improved on Bilroth’s technique. Working in the alpine mountain region provided him with innumerable patients. He performed more than 7000 thyroidectomies in his life; and was awarded with Nobel prize in the year 1909 for his contributions to thyroid surgery. Kocher in a follow-up of his patients noted that a third of his operated patients developed the features described by Gull (he called it cachexia strumipriva), and inferred that myxedema was caused by thyroid deficiency. So it was not long before George Redmayne Murray (1865-1939) in 1891 reported the improvement of a forty-six year old lady with myxedema by injection of sheep thyroid extract. And in 1895 Eugen Baumen found an iodine compound in the thyroid gland, which opened the gate for controlling goiter by addition of iodine to table salt. Such was the benefit observed in the treated patients with thyroid problems, that soon thyroid extract became the panacea for all sorts of symptoms in adults, from obesity to depression. In 1915 Edward Calvin Kendall isolated and crystallized thyroxine (also isolated cortisone and was awarded Nobel prize in 1936) the active principle of thyroid extract, and thyroid hormone supplementation became a reality. Meanwhile, Robert James Graves (1797-1853), an astute clinician keenly interested in fevers, published a paper “a newly observed affection of the thyroid gland in females” in 1835, since known as Graves’ disease, although as we know today, this condition was first described by Caleb Hilliard Parry in 1786. In the year 1893, George Oliver and Edward Sharpey-Schäfer (1850-1935) injected a dog with an adrenal gland extract and noted a sharp rise in blood pressure. Later in 1901, Jộkichi Takamine (1854-1922) and Thomas Bell Aldrich isolated the substance and designated it as ‘adrenaline’. Three years later Friedrich Stolz (1860-1936) synthesized the substance adrenaline (epinephrine in U.S.) and was the first hormone to be synthesized. Walter Bradford Cannon (1871-1945) while studying the effects of autonomic nervous system coined the term ‘homeostasis’ to mean maintenance of constancy in the ‘internal environment’, as proposed by Claude Bernard by means of various chemical substances. Thomas Addison (1793-1860), in 1849 first described what he termed as ‘melasma suprarenale’, bronzed skin associated with disease of suprarenal glands, a syndrome since known as Addison’s disease. Charles-Edouard Brown-Sequard (1817-1894, the double-hyphenated neurologist and forgotten father of endocrinology renowned for his eponymous neurological syndrome), in the year 1856 showed in animal experiments that adrenocortical deficiency is fatal and that Addison’s disease in humans involve failure of the adrenals. William Osler in the year 1896 used adrenal extract to treat one patient of Addison’s disease. William Bayliss (1860-1924) and Ernest Henry Starling (1866-1927, was born in Bombay) in 1902 conducted an experiment, which involved instilling hydrochloric acid into the dog duodenum. They noted that this activity caused the pancreas to secrete pancreatic juice. They inferred that duodenum mustbe secreting a substance in the blood that reached the pancreas. They called this putative substance as ‘secretin’. In 1905, Starling adopted the term ‘hormone’ (Greek Hormao : I excite) for all such chemical messengers that move from one organ of the body to other parts of body via bloodstream regulating various body systems. Though the effects of castration were known since ancient times, it was only in the last century that the hormones secreted by the testes and ovaries became known. It had long been known that castrating a cock led its comb to atrophy; but in 1849 Arnold Berthold showed that if the testes were transplanted in another part of the animal’s body, this did not occur. Charles-Edouard Brown-Sequard sensationally reported to the world in 1889 that injection of extracts of pig and dog testicles led to rejuvenation. The dream of recapturing the youth seemed much near and plausible, and this formed the launching pad of such flurry of ‘scientific’ activities like ‘organotherapy’ and monkey and goat testicular implants. The male sex hormone ‘androsterone’ was isolated by a German chemist Adolf Butenandt (1903-1995) in 1931, and synthesized by Leopold Ruzicka in 1934. Soon after, the Dutch scientist Ernst Laquer succeeded in isolating pure hormone from the ground-up testicles of bull and designated it ‘testosterone’. Isolation of female sex hormone was much more difficult. Edgar Allen and Edward Adalbert Doisy (1893-1986, the recipient of Nobel prize in 1943 for his work on vitamin K) in 1929 isolated the female sex hormone estrone (they called it oestrin) from urine of pregnant women. And estradiol and estriol were discovered in 1933. Progesterone was discovered a year later from corpus luteum. Synthetic progesterone was prepared from diosgenin sourced from Mexican yam (incidentally, cortisone and testosterone were also synthesized from the same Mexican yam later on) in the 1940s. In 1951, Luis Miramontes synthesized the first synthetic progestagen, norethisterone. The potential of this substance in contraception was quickly understood, and in 1957, norethynodrel was introduced in U.S. as the first oral contraceptive pill. The location and anatomy of the pituitary gland at the base of the brain was known since quite a long time, though its function was a mystery till the end of nineteenth century. In 1886, Pierre Marie (1853-1940) described a disease characterised by prognathism, overgrowth of hands and feet, and Oskar Minkowski (1858-1931) noted that in ‘acromegaly’ pituitary is enlarged, and later on Woods Hutchinson inferred that pituitary was the likely source of growth hormone in the body. In 1909, Henry Hallett Dale (1875-1968) isolated the hormone oxytocin from the posterior pituitary. Various experiments suggested that anterior pituitary has effects on many other glands of the body, and Walter Langdon-Brown described pituitary as the ‘leader of the endocrine orchestra’. Harvey Cushing (1869-1939), an outstanding neurosurgeon of his time, and avid researcher and biographer, described in 1906 relationship between pituitary tumors and sexual infantilism. And in 1932 he described a clinical syndrome named ‘hypophysial basophilism’, since known as Cushing’s disease. The brain (hypothalamus) as the source of hormones was first described by Roger Guillemin (1924-present), Andrew Schally (1926-present) and ushered in the era of neuroendocrinology (and for which they were awarded with Nobel prize in the year 1977). Diabetes was known to humanity since antiquity. And discovery of its description in an Egyptian papyrus of 1550 B.C. by Georg Ebers testifies to its long history. But the first clear description of diabetes emanated from Hindu physicians in the sixth century B.c., who clearly differentiated it (diabetes mellitus or Madhumeha ) from other causes of polyuria and sugary urine, like Udakameha (watery urine disease, i.e. diabetes insipidus) and Ikshumeha (cane sugar disease; i.e. renal glycosuria). They also gave a clear description of two types of diabetes, one which occurs in the young, characterised by a lean constitution, dehydration, increased thirst and polyuria and is due to a genetic defect and the other is characterised by stout built, increased appetite and due to injudicious way of life- quite reminiscent of today’s classification of diabetes into type 1 and type 2. The modern western description of the disease came from Aretaeus of Cappadocia in the second century, who also baptized the disease as ‘diabetes’ (Greek, meaning siphon). And the English physician Thomas Willis (1621-1675, of the Circle of Willis fame) added the term mellitus (derived from Latin root for ‘honey’, c.f. madhumeha) to distinguish it from diabetes insipidus. In the year 1776 Mathew Dobson (?-1784) described diabetes as a disease with increased sugar in the serum. In 1788, Thomas Cowley reported that diabetes may follow damage to pancreas. In 1869, Paul Langerhans (1847-1888) observed the special cells in the pancreas which bears his name, but he could not fathom the function of the same. In 1889, Oskar Minkowski and Joseph von Mering (1849-1907) removed a dog’s pancreas and found it developed diabetes. Edward Sharpey-Schäfer (1850-1935) determined that the substance needed for carbohydrate metabolism was produced in the Islets of Langerhans, and named the substance ‘insuline’ after the Latin insula (island). Isolation of the active principle of the islets was elusive, and after many attempts, Frederick Grant Banting (1891-1944) and Charles Herbert Best (1899-1978) in the year 1921, with the help of John Macleod (1876-1935) and James Collip (1892-1965) isolated insulin from a dog’s pancreas and saved the life of the pancreatectomized dog by infusing insulin, heralding a new era in endocrine therapy. On 11th January 1922, they injected for the first time a human being almost dying of diabetes (Leonard Thompson by name) with the pancreatic extracts and the boy survived. What followed was history and they were aptly and promptly awarded Nobel prize in the year 1923 for their seminal work and the epoch making discovery (Banting and Macleod were awarded Nobel prize, which they shared with Best and Collip respectively). Rosalyn Yallow (1921-present) discovered the technique of measuring extremely low concentration of substances in the plasma (for example hormones) by radioimmunoassay. And the hormone which on which this measurement technique was developed was insulin, and she was awarded Nobel prize in the year 1977 for this seminal contribution in the advancement of science.

Written by E ndocrinologyatglasgowroyalinfirmary , October 27, 2017 The interest in ‘endocrine’ glands began in antiquity when the most obvious organs accessible to the knife, the testes, were sometimes removed either to make the harem safe, or to extend the duration of the male soprano voice into adulthood. On a culinary note, testicular removal made a rooster into a capon which was much more palatable. The other common presentation of endocrine disease was thirst, copious production of urine and weight loss. Descriptions of this condition can be seen in medical literature from Egyptian papyri, and from Indian, Chinese, Greek and Arab sources. In the second Century AD, Aretaeous of Cappadocia [1] coined the name ‘diabetes’ though it was not till the 17th Century that the English anatomist and physician, Thomas Willis added ‘mellitus’ to diabetes in view of the sweet nature of the urine produced. It was, however, the emergence of anatomy and physiology as scientific disciplines that concentrated minds upon those tissues of the body which looked like glands or organs and had a rich blood supply yet had no ducts (blood-glands). [2] A Thyroid Narrative The other gland relatively accessible to the knife, particularly if enlarged, was the thyroid. The Chinese used burnt sponge and seaweed to treat goitre over many millennia. In 150 AD, Hippocrates and Plato recognised this treatment and thought that the thyroid gland lubricated the larynx. Thomas Wharton , anatomist in 1656, wrote about the anatomy of the gland that he thought it was there to heat the larynx. He named it ‘thyroid’ after the ancient Greek shield with a similar pronunciation. In German, the thyroid is ‘die Schilddrüse’, the shield gland. Two other anatomists, from Holland Frederik Ruysch in the 17th, from Switzerland Albrecht Von Haller in the 18th Century and Thomas Wilkinson King who was a physiologist in the early 19th Century Britain, each wondered whether the thyroid elaborated a secretion which was carried away by the veins. veins. Thyroid history in the 19th Century, however, was a tale of three streams which converged as knowledge of its function emerged. These streams were Iodine, Goitre and Cretinism or hypothyroidism. In 1811, the French chemist Bernard Courtois was extracting soda from burnt seaweed because of a shortage of the usual woodash. He tried to clear the deposit on the bottom of his copper extraction vessels with sulphuric acid and immediately noticed an intense violet vapour which condensed in the form of crystals. By circuitous routes, the crystals eventually reached both the French chemist Joseph Louis Gay-Lussac and, with the permission of Napoleon , Sir Humphrey Davy. Each chemist separately identified a new chemical element which they agreed to call “iode”, or iodine, from the Greek word for violet. It is not clear why iodine then became the focus for the treatment of thyroid enlargement. Initially suggested by Dr William Prout in London, 1816 [4] , it was John Elliotson from St Thomas’ Hospital who used it for goitre in 1819. In 1820, the Swiss physician Jean Francois Coindet used a tincture of iodine more widely with initial success. His treatment was questioned and fell into disrepute when some individuals developed hyperthyroidism ( Jod-Basedow syndrome). In 1825, David Scott used iodine to treat goitre in Assam, India and in 1831, the French chemist J ean-Baptiste Boussingault used iodised salt in present day Columbia for the same condition. In 1835, Caleb H Parry followed by Robert James Graves from Ireland described hyperthyroidism with goitre and noted an ophthalmopathy. The German physician Karl Adolph vonBasedow independently reported similar cases in 1840 and firmly linked hyperthyroidism with the associated ophthalmopathy. In 1851, the French physician Caspar-Adolphe Chatin discovered that certain goitrous areas of Europe were associated with a low environmental iodine. While the national scientific community in France remained sceptical about Chatin’s evidence, iodine prophylaxis for goitre began in earnest. The History of Diabetes In 1815, the French chemist Michel Eugene Chevreul in Paris showed that the sweet tasting substance in the urine of patients with diabetes was glucose. In 1848, Hermann Von Fehling , a German chemist, developed a qualitative test for glucose in urine but it was not until 1889 that the pancreas became implicated in diabetes. Oscar Minskowski and Joseph von Mering , both German and working at the University of Strasbourgh, showed that dogs in whom the pancreas was removed developed diabetes mellitus. In 1893, The Frenchman Edouard Hedon showed that grafting pancreatic tissue back into the animal prevented diabetes from occurring. Something being secreted by pancreatic tissue was important for the prevention of diabetes. In the same year, the French scientist Gustave-Edouard Laguesse wondered whether the islands of tissue left after pancreatic duct ligation that had been described in 1869 by the German pathologist Paul Langerhans, might just be the source of the substance that controlled glucose levels. The concept of internal secretion by that time was close. Contributions from Physiology and Anatomy In 1849, the German Physiologist Arnold Adolph Berthold performed a classic ‘endocrine’ experiment while studying maleness in chickens. He took 6 male chickens, castrated 4 and left 2 to develop rooster characteristics such as combs and wattles. Two castrati became chicken eunuchs or capons with soft flesh. In the final two, he transplanted the testes back into the abdominal cavity and found they developed normally as roosters. He concluded erroneously that the testes conditioned the blood to result in normal development. It was not until 1935 that pure testosterone was isolated. In 1850, Thomas Blizzard Curling correlated the absence of thyroid tissue at autopsy in two children with cretinism. Come 1855, when physiological conundrums attracted the brightest of minds, the French physiologist Claude Bernard hypothesised that the liver might somehow secrete glucose into the blood while in the same year, Thomas Addison, an Edinburgh graduate working in Guy’s Hospital , proved, by autopsy, that suprarenal gland destruction was present in 11 cases with weakness, vomiting and skin pigmentation which he understood to indicate chronic adrenal insufficiency but he was not believed at the time. In 1871, Charles Hilton Fagge presented a paper describing four children with sporadic cretinism and wondered whether the thyroid had ‘wasted’. Two years later in 1873, William Gull of Guys Hospital described hypothyroidism in adult life as creating a cretinoid appearance with a thick tongue. In 1877, William Ord described ‘mucous oedema’ and proposed the term ‘myxoedema’ for the adult condition. He also described the ‘practical annihilation’ of the thyroid gland at autopsy in these patients. A Surgical Contribution In 1882, Jaques-Louis Reverdin from Geneva and in 1883, Emil Theodor Kocher from Berne, both Swiss surgeons, noted that after total thyroidectomy, myxoedema was common. Because of this, they each experimented by conserving part of the gland during thyroidectomy, and no further cases of myxoedema occurred. [5] Although they did not understand what was happening, these surgeons had provided the medical community with the key to understanding the importance of the thyroid gland. Kocher went on to be awarded the Nobel prize for medicine in 1909 for work relating to the surgical and medical treatment of thyroid disease. In 1883, Felix Semon , a trainee laryngologist, later Sir Felix, suggested, to much ridicule from medical colleagues, that myxoedema and cretinism were one and the same condition, namely the effects of hypothyroidism. What he managed to do was to encourage his surgical colleagues to survey the experience of thyroid surgeons Europewide. Reporting in 1888 and using experimental work on thyroidectomised monkeys by Sir Victor Horsley [6] , the renowned scientist/surgeon who followed on in neurosurgery from Sir William Macewan, the report vindicated Semon and concluded that myxoedema was almost certainly due to loss of thyroid function and could lead to cretinoid features. Horsley went on to advocate surgical grafting of sheep thyroid into patients with myxoedema and in 1890, Bettencourt and Serrano of Lisbon had success with resolution of some clinical features in a case grafted under the breast. They then tried hypodermic injections of thyroid juice in 1891 and reported these beneficial too. The function of thyroid was now clear though the mechanism remained a mystery. In 1891, Horsely and Professor George Redmayne Murray also continued along these therapeutic lines and and used hypodermic injections of sheep thyroid extract into a patient with myxoedema and described a dramatic improvement. Murray provided details of his method of preparation and administration of the extract. Later that year, after publications from H. W. MacKenzie and E. L. Fox who had separately treated hypothyroid patients with thyroid extract by mouth, he changed to oral administration of pooled sheep thyroid extract with similar effect and so oral replacement therapy for glandular hypofunction was born. Parathyroids, Pituitary and Adrenal Ivar Sandstrőm , Uppsala medical student in 1887, confirmed the existence of the parathyroid glands in 50 autopsies and in 1901, the French physiologist Eugene Gley linked the absence of parathyroids after thyroid surgery to tetany which was often a sequel. [9] Although the pituitary gland had been recognised in previous years at autopsy, for instance in studies of the two Irish Giants, its clinical role was more difficult to define because of its position in the centre of the skull. Clinical interest in the pituitary gland mainly arose from the studies and description of Acromegaly by Drs Pierre Marie, French neurologist , and José Dantas de Souza-Leites from Brazil in 1886 [10] . In 1893, George Oliver was interested in extract of adrenal gland to treat low blood pressure. He listed the help of Edward Shafer , Professor of Physiology at University College, London and found that his extract greatly raised the blood pressure in dogs. They both went on to discover that the effect was due to extract of medulla and not cortex. Clearly, the important parts of the ‘endocrine’ or blood-gland jigsaw were gradually being assembled and one-by-one, the glandular origins of clinical deficiency syndromes were becoming clearer. The work on insulin, in particular, clearly pointed to a pancreatic source for a secretion of some sort preventing diabetes. The Fog Clears In 1905, the British physiologists Ernest Starling and his brother-in-law William Bayliss discovered something in the blood that caused the pancreas to secrete digestive juices. Their experiment was in two parts. Firstly, they had used a completely denervated loop of duodenum, activated it by food, and found it stimulated pancreatic juice flow. Thinking that it must be something in duodenum, they liquified duodenal mucosa, injected it into the denervated animal model and found again that pancreatic juice flowed. Starling and Bayliss realised that a substance, which they called ‘secretin’, passed from the stimulated duodenum to the pancreas to stimulate it by virtue of the circulation of blood and not by the nervous system. They confirmed this hypothesis on the second experiment. Starling proposed after consultation with a classics trained colleague that such substances were called ‘hormones’ after the Greek ‘ormao’ – to excite, and at this precise point in history, a new speciality called ‘ endocrinology ‘ emerged. It studied substances produced by one tissue and then transported by the circulation of blood to another tissue, called the target. The final part of the jigsaw, the concept of circulating hormones, had fallen into place in the early 20th century. The work by Frederick Grant Banting , Charles Best , John J R MacLeod and James Collip in extracting an insulin soup from atrophied pancreatic glands, purifying it, and by 1921, using the purified material in clinical practice was a monumental moment in the history of endocrinology. They had learned the lessons of the past and even had a name for the substance because in 1909, the Belgian physician Jean de Mayer had named the putative substance produced by the Islets of Langerhans, “insulin”. When supplies of the purified animal sourced insulin reached the UK in May 1923, they saved the life of Dr Robert (Robin) Daniel Lawrence , a Scot from Aberdeen, among many others. Lawrence became one of the first UK physicians in diabetes at King’s College Hospital, London. He later co-founded the Diabetic Association with author and historian Herbert George (HG) Wells which later became the British Diabetic Association. Although physiologists and the new ‘endocrinologists’ were unable to directly quantitate the actual hormones at this time, indirect ways were devised by them and physiologists to measure the ‘exciting’ effects of hormones on other tissues. It would be another 40 years before clinical measurement of insulin in blood would be possible but at least in 1921, there was a rational treatment for diabetes and myxoedema. References [1] Milestones in the history of diabetes mellitus: The main contributors. World Journal of Diabetes, 2016, Jan 10; 7 (1): 1-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707300/ [2] Starling Review: Ernest Starling and ‘Hormones’: An historical commentary, by John Henderson. Journal of Endocrinology, Volume 184, Issue 1, 2005, pages 5-10. http://ressources.unisciel.fr/biocell/chap11/res/03_hormone_starling_henderson.pdf [3] By courtesy of the European Thyroid Association and from the 4th Annual Meeting in Berne, 1971, President Prof H. Studer. [4] A History of Iodine Deficiency Disorder Eradication Efforts, by J Woody Sistrunk and Frits van der Haar, in ‘Iodine Deficiency Disorders and Their Elimination’, Editor Elizabeth N Pearce, Associate Professor of Medicine, Boston University School of Medicine, Boston, MA, Springer 2017. Accessed on 12 February, 2018. http://books.google.co.uk/books?id=Fo4JDgAAQBAJ&pg=PA5&lpg=PA5&dq=Chatin+endemic+goitre&source=bl&ots=KoK32iNVAi&sig=kK57jlxisqy2PsafOxFeVZFypcc&hl=en&sa=X&ved=0ahUKEwiVtITzpZ7ZAhUsC8AKHRK8BoEQ6AEIRzAG#v=onepage&q=Chatin%20endemic%20goitre&f=false [5] Hypothyroidism and Thyroid Substitution: Historical Aspects by J Lindholm and P Laurberg, 2011. Journal of Thyroid Research, Volume 2011, Article ID809341. Accessed 12th February, 2018. http://hindawi.com/journals/jtr/2011/809341/ [6] The Discovery of Thyroid Replacement Therapy. JLL Bulletin: Commentaries on the History of Treatment Evaluation. Stephan D Slater, 2010. Accessed 20 November 2017. jameslindlibrary.org/articles/the-discovery-of-thyroid-replacement-therapy/ [7] In. ‘Sir Victor Horsely, an inspiration’. BMJ. 2006; 333, 1317. [8] By courtesy of The James Lind Library. [9] The History of Parathyroids. Accessed 20th November, 2017. http://endocrinesurgeon.co.uk/index.php/the-history-of-the-parathyroids [10] In the land of Giants: the legacy of Jose Dantas de Souza Leite. Accessed 20 November, 2017. http://scielo.br/pdf/anp/v73n7/0004-282X-anp-73-7-0630 H W Gray J A Thomson

Written by Dr. Bjørn Øverbye, 2007 Original language: Norwegian In the period 1892-1958, there was only one medicine for metabolic failure: Natural Desiccated Thyroid (NDT). During this period, the doctors defined "low metabolism" as a group of disorders that could be identified via the patient's symptoms and thorough medical work, and which improved or improved with NDT. Here's how people thought at the time: With love for knowledge Let it be clear from the start: This is not a site promoting the use of Natural Thyroid (NDT) in favor of synthetic hormones. When we bring up the topic of NDT, it is solely because we are searching for knowledge about why doctors of the past could report so many positive results with NDT before you even got commercially available synthetic hormones. When the use of synthetic hormones came into general use is unclear. But it is known that Thyroxin Natrium was registered in Norway in 1950 and Synthyroid in the USA in 1958. Did the Norwegian authorities allow bad medicine for 8 years? So in Norway, 1950 is considered the year when "the new era started". This year is tainted with a somewhat curious piece of information. According to the American Drug Administration (FDA), Thyroxin-Natrium was not an FDA-approved drug before the year 2000 because its mode of action was poor. This could mean that for 8 years the Norwegian Medicines Control Authority allowed the use of a poor-quality medicine for hypothyroidism that was not approved by the FDA. Even more strange: It seems that the authorities in many states allowed the sale of Thyroxin-Natrium despite this. Today, 50 years later, it is considered in the USA that it was not until 1958 that synthetic thyroxine of good quality came on the market that could compete with NDT. The good product was called Synthyroid. (Steven B Johnson, Division of Pharmaceutical Evaluation Phase II-FDA, 13 March 2003) We have therefore chosen in this website to use 1958 as the year when reliable synthetic thyroxine (T4) became commercially available, as the year when NDT gained a credible competitor. A problem based on a misunderstanding The starting point for our search is to understand what type of medical work was carried out in the period 1892-1958 when NDT was the only therapy offered and which led the doctors to say that they observed improvements in people with metabolic diseases. What did they do that led to completely different conclusions than what opponents of NDT come up with now in recent times? In this context, we make a clear reservation: We do not believe in any praise from the past. We take advantage of the limited laboratory services of the time. We realize that today's "gold standard" double-blind placebo-controlled trials were not possible to carry out because: There was only one preparation of good quality against metabolic failure, namely NDT, until 1958. (Thyroxin-Natrium came on the market in Norway in 1950, but in the USA it is stated "in the 50s") Placebo testing was not used as it would be revealed immediately. That's because if you have a hormone deficiency, you notice that it's a dummy pill because they can't induce a hormonal effect. We therefore cannot, as many do, blame the doctors of the past for not doing as they do today. The situation was frankly incomparable. What was found of research must only be assessed as to whether it was good or bad medical work. It is the results from the doctors who did good medical work that we will examine, to see if they can give us an answer as to how good NDT was. Devotion to provable facts It is something that strikes one when one reads the positive statements in favor of NDT from 1920 onwards, when doctors such as O. P. Kimball (1933), G. K. Wharton (1939), and then B. Barnes (1976) and a number of other outstanding doctors made his observations, namely this one fact: The good doctors were faithful to a professional ethic based on devotion to reality. The good doctors were true to reality in that they had faith in the patients' stories and the changes they saw in the patient's body, which they termed as myxedema in one version or another. Second, they considered it their moral obligation to use the drug they had available, NDT, in such doses that they observed gradual improvement in the sick (Barnes 1976). Thirdly: The doctors were still working in an age when medical science was not paid by the pharmaceutical industry to prove that certain chemical industrial products should have an advantage over other products. There was only NDT. First observe, then conclude The doctors who conducted research and recorded experiences with NDT describe how they assessed the effect by listening to what the patients said about subjective improvements (symptoms) (Barnes page 24) Furthermore, by observing and touching the patients, they describe how to observe changes in the patient's body shape and body consistency (signs). In addition, to measure muscle strength. They describe what measurements they made to seek measurable effects of therapy such as: Weight Measure blood pressure. Listen to your heart Take EKG (already available 120 years ago) Woltman's sign: Delayed whole-tendon reflex (discovered in 1870) Measuring the temperature (since the 1920s) Make measurements of certain blood values that change with metabolism, such as cholesterol, the calcium index, the blood sugar load curve etc. The doctors thus had good methods for observing changes as a result of taking NDT and the dosed tablets so that the changes became increasingly similar to what we see in healthy people. Hormone tests in the blood only came much later Commercial measurements of thyroxine in the blood first came in the 1960s. The test for free thyroxine came in 1965. Commercial tests for TSH appeared in 1975, but it was not until 1985 that the TSH tests became usable. But as late as 1992 there was great disagreement among chemists and doctors about the most commonly used Free T4 tests, whether they were at all usable in clinical work. The discussion regarding whether Free T4 and TSH were in accordance with the facts continued until 2009 (John Midgely 2014). This means that well into our century, much of so-called "modern thyroid research" was fraught with major problems and that placing all trust in laboratory values was not as good as many people today think. Doctors must learn from nuclear physics The first generations of thyroid doctors were therefore dependent on observing the results of actions. This is also consistent with another discovery made at the end of the nineteenth century in atomic physics that made physics a brilliant success: The physicist realized that you could not comment on something until it had happened. (Feynman 1963) In physics, it became clear that no one can predict what will happen at the atomic level without measurements. This was the reason why many inventive atomic theories that were made before having good measurements were discarded, because the inventive theorists could not provide measurements that supported their assumptions. (Feynman 1963) Physicists understood that you have to measure what you have to say about, whatever that may be. This became the cornerstone of physics. You cannot create a theory/mental images accompanied by mathematical models until you have measurement data. Therefore, contemporary physicists were horrified when Einstein stated that mystical experiences were a path to knowledge. This meant that Einstein did not receive the Nobel Prize for his theory of relativity, because he claimed to have constructed it on principles that had not yet been explained by measurement. He did, however, get it for the explanation of Planck's photo-electric experiment. Medicine is not science until one has observed This will necessarily also apply to the medicine, you cannot comment on a medicine until you have measured its effect on the individual patient. The observations must then be able to be described in understandable language that points to a recognizable reality. (Korzybski 1994) Since people's ability to react to a drug depends on a number of factors, the measured and observed effect will depend entirely on what the patient experiences and the doctor records. It is therefore virtually impossible to carry out medical activities, dose the sick with standard doses, and forget the basis for objective materialistic science, namely the ability to observe. The doctor must train patients to understand what is happening in their own body so that the patient can tell the doctor what is happening. The doctor must then observe what is happening. (Skrabanek and McCormick). One cannot have any meaningful conversation about NDT versus Thyroxine and whether one is better than the other. One can only determine the observations made by the patient himself and by the doctor using medical tools. Therefore, according to Professor Broda Barnes and others with him; without accurate observation made by patients and by doctors with their tools, there is no basis for a credible expression of opinion in a debate or in argumentation in front of patients and colleagues. Continuing this logical consideration, we ask you who are reading this; Does a person get better with synthetic hormone than with NDT? What will this person then use? Someone else only gets better with NDT and not with synthetic hormone, what should this person use? We leave the conclusions to the reader, because this was intended as a summary of historical facts and not a discussion of one versus the other.

Written by Dr Bjørn J Øverbye 2017 Original language: Norwegian   Until 1958, there was only one therapy option: Natural dessicated thyroid called NDT. Until 1970 there were no good commercial lab tests for hormones. The medical profession was a practical craft on the patient's terms. But during the period 1958-1975 we had a completely new situation, which was experienced as it is now for more and more patients: Why do I have symptoms of hypothyroidism when the laboratory tests are normal? Brief history lesson Below is the timeline of some relevant data for this article. Data on testing is taken from Dr. Midgley's eminent lecture in 2014. 1810-1893: Goiter was treated with iodine. 1888: A treatise on hypothyroidism was prepared, based on reports from 64 surgeons across Europe, about the deterioration of patients' health when the thyroid gland is removed. 1893-1958: Natural thyroid in tablet form (later called NDT) which is an extract from a gland in pigs, cattle or sheep was used in therapy. 1950: The medicine Natrium Thyroid came on the market, but was very unstable and unpredictable, and doctors continued with NDT. 1958: The first usable synthetic thyroxine (T4), Synthyroid hit the market. (Knoll Pharma, later acquired by Abbot) On the website for Synthyroid there is an error. It says that synthetic thyroid has been available since 1927. This is the year when synthetic thyroxine was first made in a laboratory, but it was not until 1950 that sodium thyroxine was made for sale. The first commercial product was of poor quality. Only with Synthyroid did you get a better product. NDT is slowly being phased out during this period, but is still used by many doctors to this day. NDT is now experiencing a renaissance among patients who do not have the desired/expected improvement from synthetic hormone. 1960: The first commercial tests to measure thyroxine became available. Until this year, clinical assessments and patients' symptoms were dominant in diagnoses of various degrees of hypothyroidism. 1963-1965: The first effective tests to calculate free thyroxine (FT4) arrived. Unfortunately, the first methods for calculating FT4 were not very good and it would take many years before they became reliable. 1975: The first commercial tests for TSH and T3 hit the market. A few years later, tests for FT3 come. The period 1958–1975 was therefore two decades that would change everything that doctors believed about metabolism and which is brilliantly described by Broda Barnes in his historical and analytical book: "Hypothyroidism: The Unsuspected Illness". In this book, Barnes talks about a problem we still struggle with and which can be described very simply: Back when doctors trusted the patient Until 1975, most doctors relied on clinical assessment of patients. This included a careful symptom analysis and various clinical tests that all doctors could do in their office. When this information was compared, the doctor then made a decision and prescribed either NDT or synthetic thyroxine. Systems analysis: What doctors should learn from computer engineers This way of working is similar to that found in physics, chemistry and not least the engineering profession. The method is called system analysis and was developed by a number of mathematicians and physicists and is the basis of cybernetics; computer mathematics. The term system can be anything from a machine, to a plant, an animal or an ecosystem. To describe the system, you need system parameters: measurable variables that are typical of the system. You can then monitor the system by constantly taking measurements of the variable units and studying changes and seeing how these change when the system is exposed to various external influences. This may seem a bit theoretical, but immediately becomes practical when it comes to working with human health. To understand what happened when the thyroid gland failed, the old doctors used a series of observations and measurements which together are variables that describe the "system", i.e. your total mental and physical performance, and physically measurable changes in the body's blood pressure, reflexes and blood values. But again, it wasn't until the late 1960s that you could measure thyroxine in the blood in a reliable way and only in 1975 you could measure TSH and T3. This means that for 80 years doctors were without chemical analyzes they could rely on. Metabolism was and became a craft: System description, giving hormones and observing changes, without having measurements of hormones in the blood to navigate by. And what did you learn? According to historical sources, people got better. And more people benefited from therapy than we see today when doctors only navigate by blood values (Barnes 1976). A new generation takes an interest in lab chemistry But why did it happen that younger doctors began to overlook clinical work if we assume the standard used by older doctors? It all depends on what we call beliefs about metabolism. When doctors could measure the value of thyroid hormones, it was believed that they had a measure of what the cells would receive and that the clinical result would therefore be predictable. This was certainly true for some patients and gave the doctors a useful tool, but it was not true for all. Why? Professor Karl Popper's 100 white swans The skeptics and doctors Petr Skrabanek and James McCormick have told this in an ironic and entertaining way in the book "Medical Mistakes and Follies" by, among other things, referring to the philosopher of science Karl Popper. Karl Popper often argued that the medical profession did not meet the criteria of an exact science because it was too approximate. To illustrate one of science's major problems that Petr Skrabanek and James McCormick believe is highly relevant to doctors' understanding of the world, they draw on Popper's equation called the "hundred white swans' fallacy". A scientist observes swans and after 100 observations finds that they are all white. He writes a thesis in which he claims that "all swans are white". But one day he observes a black swan (which does exist) and the whole claim has to be rejected and replaced with: "Swans can be black or white". He must further specify this more carefully; "More white swans than black swans have been observed". The black swans of metabolic medicine The same applied to metabolic medicine in the critical years (1958-1975) when younger doctors decided to discard the experiences of the previous two generations. It was observed that in most patients, laboratory tests were a simple and straightforward way to see who benefited from synthetic hormone. This meant that more and more doctors began to disregard system description, i.e. clinical skills and overlook that NDT could be used where synthetic hormone did not reach its goals. In other words, they had made the mistake Karl Popper warned against. They had observed 100 white swans, but began to overlook that around them a number of black swans also began to appear; Patients with clinically manifested hypothyroidism defined according to the old method which is as follows: Those who meet a number of specific criteria to be able to receive thyroid hormones and get better from enough hormone over time. The black swans were those who actually qualified for treatment, but had "normal blood values". Why we should treat Shouldn't that "ring some bells"? Yes, with the good clinicians, warning bells rang. But according to Broda Barnes and those who thought like him, it became fashionable among younger doctors to disregard the time-consuming part of the medical profession; to make thorough examinations and listen to the sick. Instead, many began to look at a lab sheet and conclude then and there that the patient had hypothyroidism or not. Over two decades, it was forgotten that metabolism means manifestations of failing energy production to simply mean "a certain amount of thyroid hormone", which after all is just one of several hormones and chemical conditions that regulate energy production in the body. And many of the other conditions affect the effect of thyroid hormones, so the values of thyroid hormones measured in the blood are no longer enough to maintain energy production in the cells. (Øverbye 2007) The doctors change their belief system These black swans were created by a change in doctors' belief systems. According to the older doctors, the younger ones began to think convenience over solid craftsmanship. And the black swans of metabolic medicine kept increasing, but they got to sail their own sea. And where did they sail to? According to Broda Barnes' book, the many misunderstood and untreated metabolic diseases entered psychiatry, many developed heart disease, many suffered arthritis, weight problems, states of exhaustion. When John C Lowe's work became known, it became clear that a growing wave of fibromyalgia sufferers was also among the many black swans. The problems began to pile up, not to the benefit of the sick. But not without a certain benefit for the pharmaceutical industry. During this period, the industry began to develop ever-new symptom-relieving drugs that could provide some relief, where the right dose of thyroid hormone in the old days offered full or partial healing. Hypothyroidism into oblivion? By the end of the critical years, doctors' understanding had been turned upside down. Clinical work no longer became so interesting for the younger generation of doctors. Lab values began to dominate. Quick solutions became the tune of the time and doctors could take more and more consultations per day and "treat" more patients, and refer to good craftsmanship by pointing out that the lab values had become normal after all. Some improved, but a large number of patients did not experience the claimed improvement. There were simply too many black swans in the doctors' small lake, and when fewer and fewer of the black swans gave justice, it was also not noted in journals and published in journals that these were not clinically investigated and had clear measurable signs of energy failure. Many called this development progress. But Barnes wrote: "Many began to swear to lab tests, but many of us were only sworn (were cursed)" Copyright Bjørn J Øverbye 2017

Written by Nora.Heime.net Full link: https://www.nora.heime.net/armourthyroid_history.html About the history of Thyroxine and Thyroid, Erfa Thyroid (formerly: Pfizer Canada) dessicated thyroid, Thyreoidum, Thyreodinum etc. The standard is Thyroid, dried pig gland. All research on Thyroxin was actually done on Thyroid, because in the old days there was no T4, but diligent research was done on Thyroid, which was also called Thyroxine because people didn't know any better. This is called Thyroid USP (United States Pharmacopeia) where the content of thyroxine and liothyronine is now strictly regulated. In the old days, T4 and T3 were not known, so it was regulated according to iodine content. A 10% deviation in strength is permitted. (90%-110%) This applies to all Thyroxine preparations, and all other medicines. For generics, 80-125% applies. There is no generic for Thyroid, therefore the 10 percent applies. (Updated: it's been changed now, to 95-105%) Thyroid was standardized early on and produced as brands. An example available on the internet is Merck thyroidinum. In the beginning, the requirement was that it should be analyzed for iodine content, later when it was possible, of course, the amount of Levothyroxine and Liothyronine was measured. Here is an interesting Cuban website where they list all the old names and manufacturers of Thyroid: http://www.sld.cu/servicios/medicamentos/medicamentos_list.php?id=399 See also http://hypotyreos.info/behandling/naturligt-skoeldkoertelhormon List of old and new medicines: Name Country Manufacturer Thyranon Sweden Organon http://hypotyreos.info/behandling/naturligt-skoeldkoertelhormon Thyreoïdum Denmark, Netherlands Biofac Kastrup, imported to Netherlands by BUFA/Fargo Thyroidin Germany Merck http://www.thyrolink.com/servlet/PB/menu/1354910/index.htm l Armour Thyroid USA Several over times: USV, Pfizer, Forest, now acquired by Activas Pharmaceuticals NP Thyroid USA Acella Pharmaceuticals Nature-Throid, Westhroid Pure USA Western Reseach Laboratories http://www.rlclabs.com these got a central approval in the 2000's of Nature-throid in the UK and went throught all these approval procedures http://getrealthyroid.com ERFA Thyroid Canada Parke-Davis, acquired by Erfa (flagship: Belgia) Thyroid Powder, USP Canada Medisca (only available through compounding pharmacies) Cinetic Italy Teofarma SRL Thyreoid Germany ​ Tiroides Spain ​ ? Japan ​ Thyroidine France ​ Thyroid-S Thailand Sriprasit Thiroyd Thailand Greater Pharma Thyroid API Spain Bioiberica Adthza USA Azurity Pharmaceuticals Thyrid Extract Australia Australian Custom Pharmaceuticals Compound Thyroid Denmark Glostrup Apotek Thyreogland Germany Klösterl-Apotheke, Munchen Schilddruesen-Extrakt Germany Receptura Whole Thyroid New Zealand Pharmaceutical Compounding New Zealand Diotroxin South Africa Aspen Pharmacare Ltd Generic Thyroid USA Major Pharmaceuticals Qualitest USA Time-Caps Labs Thyrolar USA Forest Labs Thyrogold USA Natural Thyroid Solution (non prescr. but recommended by Dr. Lowe) Some of these are no longer available on the market. Thyroid USP has content of T4 and T3 that is strictly regulated, that's what USP means, United States Pharmacopeia. The specification zone is that 1 grain contains 38 mcg T4 plus 9 mcg T3, plus or minus 10%. This is completely reliable. 1 grain = 60 mg. In Europe, Thyreoïdum and other similar products do not have this requirement, but all batches of Thyreoidum from Denmark are analyzed and the amount of T4 and T3 is specifically stated. So there is not even 10% wiggle room. There is a higher proportion of T3 in Thyroidum. This is probably what Wiersinga is getting at. But his statement is being used about the unreliability of Armor Thyroid by Welsh in Australia and William Harper in Canada here. Wiersinga is based in Holland, Welsh in Australia, and Harper in Canada. In Australia there is no Armour, they use powder from the USA and the pharmacies make capsules. In Holland they use Thyreoïdum, and in Canada there is no Armour, they make their own, but from imported raw material. (It was Pfizer that owned Armor Thyroid at the time, and then Pfizer split up into Canada and the US and so Canada got the original old Armor formulation before all the reformulations. Armor got no rights for marketing abroad, it was Thyroid in Canada who received. Then Erfa bought up a bunch of rights, and bet on Thyroid based on patient wishes. It is approved by Health Canada, which is important for us in Europe since it is often a prerequisite that the medicine must be approved in the country of origin for it to be approved in Europe at all) Here in Europe we had Merck Thyroidin according to their own website, but I don't have an overview of all the brands that existed, I have found a brand from Switzerland as well. Thyroidum is still made in Denmark, it is what the Dutch patients use today. Armor Thyroid from Forest does not have rights outside the US, not even Canada. It came about because Pfizer, who owned the rights, was split up in the US and Canada and they split up the rights to Armor and Thyroid. Thyroid from Canada is the original Armor due to the old rights. Western Research Laboratories has been approved (central approval, but everyone must apply for a registration exemption, which is called named-patient program in foreign languages) for their brand Nature-Throid here in Europe, they went through the approval procedure in England and it therefore applies throughout Europe. It is just as reliable. Everything comes from the same raw material. http://thyroid.about.com/cs/thyroiddrugs/a/naturethroid.htm What distinguishes the American USP (United States Pharmacopeia) Thyroid from the European one is that the ratio between T4 and T3 is constant and that the strength is the same all the time, which is an advantage when making pills from it. (Comment from a pharmacist at Stenlake Pharmacy in Australia). The European Thyroidum has varying strengths and ratios of T4 to T4 for each batch, which lasts approximately one year. On direct request to the users, they say that it has no consequences (the forum in Holland). In addition, Thyroid is still available in Japan and Thailand. Updated: According to their own forum, Erfa says that they obtained Thyroid raw material in Europe. It may well be from biofac in Denmark, and tens of millions of pig glands are exported from Denmark, according to a Dane on Sonja's Stoffskifteforum. They can therefore presumably make Thyroid with USP specifications as well. In any case, the effect is absolutely excellent according to all patients who have tried it. The amount of active ingredient is also stated as less than Armour had, but the effect is the same as old Armor from when it was good. Other patients have also noted that for Levothyroxine, the effect of European tablets was stronger than that of American ones. Now it was thought that thyroxine (=t4) was the active substance in Thyroid, and levothyroxine (=t4) came on the market. It was claimed to be exactly the same as Thyroid. Double blind tests were never conducted to prove that Levothyroxine worked as well on the patients as Thyroid for that reason (Note that at least 14 comparison studies have been done). That is the reason why today we cannot show double blind tests that Armor Thyroid is as effective as Thyroxin, or that patients in such tests felt better or worse. It comes from the makers of Thyroxin who all along claimed it was the same as Thyroid. Update: Dr. Lowe has found at least 14 direct comparisons of Thyroid vs Thyroxin in the literature. He says it is wrong, a repeated lie, that there are no comparative studies between the two. Thyroid was recognized as stable and effective. Then came a clean-up of medicines in the United States. All that had been used for many years and proved effective were given the status of approved on historical grounds. Note that when applying for approval in Norway, an exception may be granted to submit documentation in clinical trials, namely historical use. Digitalis and Thyroid are just such remedies. Synthroid, as thyroxine was called in the US, claimed historical status and referred to Thyroid, that it was the same as Thyroid. They managed to get away with it until the FDA cut through and decided that all Levothyroxine products were new drugs and that they had to go through new approval procedures and prove their shelf life and dose stability. Synthroid was notorious for repeatedly changing the ingredients and active substances and that the strength could be much more or less than stated. Many patients were very dissatisfied because they became so unwell that they functioned poorly at work etc. A bigger scandal was also the case where Knoll, who owned Synthroid, then prevented a research report that was to be printed, stating that Synthroid was no better than other brands. It was such a big scandal when it came out that they fired the researcher and prevented the publication of correctly conducted research. And then there was a larger compensation case in the wake of this, where the patients got back a few dollars for the overcharge they had to pay, when in reality all Levothyroxine preparations were equal. The patients had paid a huge premium because Synthroid had claimed to be far superior to the others. Synthroid costs about 52 dollars for 90 tablets compared to Thyroxine in England about £2.50 and Levaxin here about NOK 70 for 100 tablets. Synthroid is known to be inconsistent, not Thyroid. If you search the database for recalls in the USA, it is Levothyroxine that has been recalled, not Thyroid. The different brands of Levothyroxine, despite the fact that they should contain the same, should not be used interchangeably because they will give different blood values. If you switch, you must take new blood tests after 6 weeks. The various manufacturers of Levothyroxine fought for many years against having to apply for approval. They constantly claimed that their product was identical to Thyroid, which was recognized as stable and with good effect. NDA = New Drug Application. Approval on historic grounds is called "Grandfathered In". References: http://thyroid.about.com Have followed closely the questions about metabolic drugs. http://thyroid.about.com/cs/synthroid1/a/potency.htm Note that the Federal Register is the most official thing that can be done in the US, it is where new laws are registered. A rather important document on the instability of Levothyroxine. Nobody can come here and come here and say that it is a lie that Levothyroxine is unstable. It is Levothyroxine and not Thyroid USP that is unreliable and unstable. http://www.pharmabiz.com/article/detnews.asp?Arch=&articleid=6645§ionid=14 Abbott submits NDA application. http://www.medscape.com/viewarticle/433848 About the history, Thyroid extract etc. http://www.thyroid-info.com/drugs/index.htm A brief overview of medications in the United States including Thyrolar. http://thyroid.about.com/cs/synthroidlawsuit/a/settlement.htm More on the Synthroid and Boots/Knoll scandal and trial. "In April of 1997, the Journal of the American Medical Association (JAMA) published a study, commissioned by Knoll, that concluded that Synthroid -- a synthetic thyroid hormone -- is no better than two generic alternatives or the brand-name drug Levoxyl . Knoll disagreed with the study, and considered suing to stop its publication. Betty Dong, the researcher at the University of California at San Francisco who conducted the study, told the journal that Knoll had suppressed her findings for more than six years." http://thyroid.about.com/cs/thyroiddrugs/a/unithroidapp.htm Unithyroid approved as the first L-Thyroxine preparation in 2000. http://www.medscape.com/viewarticle/410695_4 2001 "Levothyroxine sodium tablets are also currently not listed in the Orange Book. In the words of the FDA, "Levothyroxine sodium was first introduced into the market before 1962 without an approved NDA, apparently in the belief that it was not a new drug. " See also below for an explanation of bioequivalence. http://www.medscape.com/viewarticle/406824 2001 Synthroid still not approved: FDA is penalizing companies that filed late for approval of Levothyroxine Sodium products by forcing reductions in distribution over the next 2 years. http://www.centerwatch.com/patient/drugs/dru792.html Synthroid approved 2002 http://thyroid.about.com/od/thyroiddrugstreatments/l/blfdarpt.htm Among other things http://www.medscape.com/druginfo/monograph?cid=med&drugid=7033&drugname=Synthroid+Oral&monotype=monograph&print=1 "The US Food and Drug Administration (FDA) states that all approved levothyroxine sodium preparations should be considered therapeutically in equivalent unless equivalence has been established and noted in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)." http://www.medscape.com/viewarticle/410695 More about innovative drugs og generic drugs "In 1980, the FDA first published a list of approved drugs, consisting of innovator drugs approved through the NDA process and the generic products considered by the FDA to be therapeutically equivalent to these innovator products." http://www.fda.gov/foi/warning_letters/g4190d.html (no longer exists, has been replaced by a new warning) an example of an FDA warning that one must apply for approval http://www.fda.gov/OHRMS/DOCKETS/98fr/992636gd.pdf PDF about the application process from the FDA http://www.fda.gov/ohrms/dockets/dockets/05p0411/05P-0411-EC1889.html Letter to FDA from Finland about Armor Thyroid http://thyroid.about.com/cs/thyroiddrugs/l/blletter.html About a patient who prefers Armor Thyroid over synthroid etc.

ARMOUR THYROID- thyroid, porcine tablet Allergan, Inc. Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA. ---------- Armour Thyroid (thyroid tablets, USP) Rx only DESCRIPTION Armour Thyroid (thyroid tablets, USP)* for oral use is a desiccated thyroid extract that is derived from porcine thyroid glands. (T3 liothyronine is approximately four times as potent as T4 levothyroxine on a microgram for microgram basis.) They provide 38 mcg levothyroxine (T4) and 9 mcg liothyronine (T3) per grain of thyroid. The inactive ingredients are calcium stearate, dextrose, microcrystalline cellulose, sodium starch glycolate and opadry white. Armour Thyroid may have a strong, characteristic odor due to its thyroid extract component. CLINICAL PHARMACOLOGY The steps in the synthesis of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone, TSH) secreted by the anterior pituitary. This hormone’s secretion is in turn controlled by a feedback mechanism effected by the thyroid hormones themselves and by thyrotropin releasing hormone (TRH), a tripeptide of hypothalamic origin. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the normal gland’s secretion. The mechanisms by which thyroid hormones exert their physiologic action are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system in the body and are of particular importance in the development of the central nervous system. The normal thyroid gland contains approximately 200 mcg of levothyroxine (T4) per gram of gland, and 15 mcg of liothyronine (T3) per gram. The ratio of these two hormones in the circulation does not represent the ratio in the thyroid gland, since about 80% of peripheral liothyronine (T3) comes from monodeiodination of levothyroxine (T4). Peripheral monodeiodination of levothyroxine (T4) at the 5 position (inner ring) also results in the formation of reverse liothyronine (T3), which is calorigenically inactive. Liothyronine (T3) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation, hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing what has been called the “T3 thyronine syndrome.” Pharmacokinetics – Animal studies have shown that levothyroxine (T4) is only partially absorbed from the gastrointestinal tract. The degree of absorption is dependent on the vehicle used for its administration and by the character of the intestinal contents, the intestinal flora, including plasma protein, and soluble dietary factors, all of which bind thyroid and thereby make it unavailable for diffusion. Only 41% is absorbed when given in a gelatin capsule as opposed to a 74% absorption when given with an albumin carrier. Depending on other factors, absorption has varied from 48 to 79% of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors, (children’s soybean formula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss. Liothyronine (T3) is almost totally absorbed, 95% in 4 hours. The hormones contained in desiccated thyroid extract preparations are absorbed in a manner similar to the synthetic hormones. More than 99% of circulating hormones are bound to serum proteins, including thyroid- binding globulin (TBg), thyroid-binding prealbumin (TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. The higher affinity of levothyroxine (T4) for both TBg and TBPA as compared to liothyronine (T3) partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity. Deiodination of levothyroxine (T4) occurs at a number of sites, including liver, kidney, and other tissues. The conjugated hormone, in the form of glucuronide or sulfate, is found in the bile and gut where it may complete an enterohepatic circulation. 85% of levothyroxine (T4) metabolized daily is deiodinated. INDICATIONS AND USAGE Armour Thyroid (thyroid tablets, USP) are indicated: 1. As replacement or supplemental therapy in patients with hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. This category includes cretinism, myxedema, and ordinary hypothyroidism in patients of any age (children, adults, the elderly), or state (including pregnancy); primary hypothyroidism resulting from functional deficiency, primary atrophy, partial or total absence of thyroid gland, or the effects of surgery, radiation, or drugs, with or without the presence of goiter; and secondary (pituitary), or tertiary (hypothalamic) hypothyroidism (See WARNINGS). 2. As pituitary TSH suppressants, in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s), multinodular goiter, and in the management of thyroid cancer. CONTRAINDICATIONS Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis, and apparent hypersensitivity to any of their active or extraneous constituents. There is no well-documented evidence from the literature, however, of true allergic or idiosyncratic reactions to thyroid hormone. WARNINGS Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects. The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism. The active ingredient in Armour Thyroid (thyroid tablets, USP) is derived from porcine (pig) thyroid glands of pigs processed for human food consumption and is produced at a facility that also handles bovine (cow) tissues from animals processed for human food consumption. As a result, a potential risk of product contamination with porcine and bovine viral or other adventitious agents cannot be ruled out. No cases of disease transmission associated with the use of Armour Thyroid (thyroid tablets, USP) have been reported. PRECAUTIONS General — Thyroid hormones should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of occult cardiac disease. In these patients, therapy should be initiated with low doses, i.e., 15-30 mg Armour Thyroid (thyroid tablets, USP). When, in such patients, a euthyroid state can only be reached at the expense of an aggravation of the cardiovascular disease, thyroid hormone dosage should be reduced. Thyroid hormone therapy in patients with concomitant diabetes mellitus or diabetes insipidus or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required. The therapy of myxedema coma requires simultaneous administration of glucocorticoids (See DOSAGE AND ADMINISTRATION). Hypothyroidism decreases and hyperthyroidism increases the sensitivity to oral anticoagulants. Prothrombin time should be closely monitored in thyroid-treated patients on oral anticoagulants and dosage of the latter agents adjusted on the basis of frequent prothrombin time determinations. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis. Information for the Patient — Patients on thyroid hormone preparations and parents of children on thyroid therapy should be informed that: 1. Replacement therapy is to be taken essentially for life, with the exception of cases of transient hypothyroidism, usually associated with thyroiditis, and in those patients receiving a therapeutic trial of the drug. 2. They should immediately report during the course of therapy any signs or symptoms of thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness, or any other unusual event. 3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need readjustment as thyroid hormone replacement is achieved. If thyroid medication is stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such patients. 4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be measured frequently to determine if the dosage of oral anticoagulants is to be readjusted. 5. Instruct patients to discontinue biotin or any biotin-containing supplements for at least 2 days before thyroid function testing is conducted. 6. Partial loss of hair may be experienced by children in the first few months of thyroid therapy, but this is usually a transient phenomenon and later recovery is usually the rule. Laboratory Tests — Treatment of patients with thyroid hormones requires the periodic assessment of thyroid status by means of appropriate laboratory tests besides the full clinical evaluation. The TSH suppression test can be used to test the effectiveness of any thyroid preparation bearing in mind the relative insensitivity of the infant pituitary to the negative feedback effect of thyroid hormones. Serum T4 levels can be used to test the effectiveness of all thyroid medications except T3. When the total serum T4 is low but TSH is normal, a test specific to assess unbound (free) T4 levels is warranted. Specific measurements of T4 and T3 by competitive protein binding or radioimmunoassay are not influenced by blood levels of organic or inorganic iodine. Drug Interactions — Oral Anticoagulants – Thyroid hormones appear to increase catabolism of vitamin K- dependent clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started. If a patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy. Insulin or Oral Hypoglycemics – Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy. Cholestyramine or Colestipol – Cholestyramine or colestipol binds both levothyroxine (T4) and liothyronine (T3) in the intestine, thus impairing absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily removed. Therefore four to five hours should elapse between administration of cholestyramine or colestipol and thyroid hormones. Estrogen, Oral Contraceptives – Estrogens tend to increase serum thyroxine-binding globulin (TBg). In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine (T4) may be decreased when estrogens are started thus increasing thyroid requirements. However, if the patient’s thyroid gland has sufficient function, the decreased free levothyroxine (T4) will result in a compensatory increase in levothyroxine (T4) output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen-containing oral contraceptives are given. Drug/Laboratory Test Interactions — The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations, and the numerous preparations containing salicylates. 1. Changes in TBg concentration should be taken into consideration in the interpretation of levothyroxine (T4) and liothyronine (T3) values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens, and estrogen-containing oral contraceptives increase TBg concentrations. TBg may also be increased during infectious hepatitis. Decreases in TBg concentrations are observed in nephrosis, acromegaly, and after androgen or corticosteroid therapy. Familial hyper- or hypo- thyroxine-binding-globulinemias have been described. The incidence of TBg deficiency approximates 1 in 9000. The binding of levothyroxine by TBPA is inhibited by salicylates. 2. Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing. 3. Medicinal or dietary iodine interferes with all in vivo tests of radio-iodine uptake, producing low uptakes which may not be relative of a true decrease in hormone synthesis. 4. The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance to thyroid hormone is quite rare. Carcinogenesis, Mutagenesis, and Impairment of Fertility — A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroid for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females. Thyroid hormones do not readily cross the placental barrier. The clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy. Nursing Mothers — Minimal amounts of thyroid hormones are excreted in human milk. Thyroid is not associated with serious adverse reactions and does not have a known tumorigenic potential. However, caution should be exercised when thyroid is administered to a nursing woman. Pediatric Use — Pregnant mothers provide little or no thyroid hormone to the fetus. The incidence of congenital hypothyroidism is relatively high (1:4,000) and the hypothyroid fetus would not derive any benefit from the small amounts of hormone crossing the placental barrier. Routine determinations of serum T4 and/or TSH is strongly advised in neonates in view of the deleterious effects of thyroid deficiency on growth and development. Treatment should be initiated immediately upon diagnosis, and maintained for life, unless transient hypothyroidism is suspected; in which case, therapy may be interrupted for 2 to 8 weeks after the age of 3 years to reassess the condition. Cessation of therapy is justified in patients who have maintained a normal TSH during those 2 to 8 weeks. ADVERSE REACTIONS Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare (See OVERDOSAGE). OVERDOSAGE Signs and Symptoms — Excessive doses of thyroid result in a hypermetabolic state resembling in every respect the condition of endogenous origin. The condition may be self-induced. Treatment of Overdosage — Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after thyroid suppression. Treatment of acute massive thyroid hormone overdosage is aimed at reducing gastrointestinal absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Vomiting may be induced initially if further gastrointestinal absorption can reasonably be prevented and barring contraindications such as coma, convulsions, or loss of the gagging reflex. Treatment is symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, particularly propranolol, have been used advantageously in the treatment of increased sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 mg, over a 10-minute period or orally, 80 to 160 mg/day, initially, especially when no contraindications exist for its use. Other adjunctive measures may include administration of cholestyramine to interfere with thyroxine absorption, and glucocorticoids to inhibit conversion of T4 to T3. DOSAGE AND ADMINISTRATION The dosage of thyroid hormones is determined by the indication and must in every case be individualized according to patient response and laboratory findings. Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results. Inquire whether patients are taking biotin or biotin-containing supplements. If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels (see PRECAUTIONS). Thyroid hormones are given orally. In acute, emergency conditions, injectable levothyroxine sodium (T4) may be given intravenously when oral administration is not feasible or desirable, as in the treatment of myxedema coma, or during total parenteral nutrition. Intramuscular administration is not advisable because of reported poor absorption. Hypothyroidism — Therapy is usually instituted using low doses, with increments which depend on the cardiovascular status of the patient. The usual starting dose is 30 mg Armour Thyroid (thyroid tablets, USP), with increments of 15 mg every 2 to 3 weeks. A lower starting dosage, 15 mg/day, is recommended in patients with long-standing myxedema, particularly if cardiovascular impairment is suspected, in which case extreme caution is recommended. The appearance of angina is an indication for a reduction in dosage. Most patients require 60 to 120 mg/day. Failure to respond to doses of 180 mg suggests lack of compliance or malabsorption. Maintenance dosages 60 to 120 mg/day usually result in normal serum T4 and T3 levels. Adequate therapy usually results in normal TSH and T4 levels after 2 to 3 weeks of therapy. Readjustment of thyroid hormone dosage should be made within the first four weeks of therapy, after proper clinical and laboratory evaluations, including serum levels of T4, bound and free, and TSH. Liothyronine (T3) may be used in preference to levothyroxine (T4) during radio-isotope scanning procedures, since induction of hypothyroidism in those cases is more abrupt and can be of shorter duration. It may also be preferred when impairment of peripheral conversion of levothyroxine (T4) and liothyronine (T3) is suspected. Myxedema Coma — Myxedema coma is usually precipitated in the hypothyroid patient of long-standing by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances and possible infection besides the administration of thyroid hormones. Corticosteroids should be administered routinely. Levothyroxine (T4) and liothyronine (T3) may be administered via a nasogastric tube but the preferred route of administration of both hormones is intravenous. Levothyroxine sodium (T4) is given at a starting dose of 400 mcg (100 mcg/mL) given rapidly, and is usually well tolerated, even in the elderly. This initial dose is followed by daily supplements of 100 to 200 mcg given IV. Normal T4 levels are achieved in 24 hours followed in 3 days by threefold elevation of T3. Oral therapy with thyroid hormone would be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication. Thyroid Cancer — Exogenous thyroid hormone may produce regression of metastases from follicular and papillary carcinoma of the thyroid and is used as ancillary therapy of these conditions with radioactive iodine. TSH should be suppressed to low or undetectable levels. Therefore, larger amounts of thyroid hormone than those used for replacement therapy are required. Medullary carcinoma of the thyroid is usually unresponsive to this therapy. Thyroid Suppression Therapy — Administration of thyroid hormone in doses higher than those produced physiologically by the gland results in suppression of the production of endogenous hormone. This is the basis for the thyroid suppression test and is used as an aid in the diagnosis of patients with signs of mild hyperthyroidism in whom base line laboratory tests appear normal, or to demonstrate thyroid gland autonomy in patients with Grave’s ophthalmopathy. 131I uptake is determined before and after the administration of the exogenous hormone. A 50% or greater suppression of uptake indicates a normal thyroid-pituitary axis and thus rules out thyroid gland autonomy. For adults, the usual suppressive dose of levothyroxine (T4) is 1.56 mcg/kg of body weight per day given for 7 to 10 days. These doses usually yield normal serum T4 and T3 levels and lack of response to TSH. Thyroid hormones should be administered cautiously to patients in whom there is strong suspicion of thyroid gland autonomy, in view of the fact that the exogenous hormone effects will be additive to the endogenous source. Pediatric Dosage — Pediatric dosage should follow the recommendations summarized in Table 1. In infants with congenital hypothyroidism, therapy with full doses should be instituted as soon as the diagnosis has been made. Table 1: Recommended Pediatric Dosage for Congenital Hypothyroidism Age Armour Thyroid (thyroid tablets, USP) Dose per day Daily dose per kg of body weight 0-6 months 15-30 mg 4.8-6 mg 6-12 months 30-45 mg 3.6-4.8 mg 1-5 years 45-60 mg 3-3.6 mg 6-12 years 60-90 mg 2.4-3 mg Over 12 years Over 90 mg 1.2-1.8 mg HOW SUPPLIED Armour Thyroid (thyroid tablets, USP) are supplied as follows: 15 mg (1/4 grain) are available in bottles of 100 (NDC 0456-0457-01 or NDC 0456-1045- 01). 30 mg (1/2 grain) are available in bottles of 100 (NDC 0456-0458-01) and unit dose cartons of 100 (NDC 0456-0458-63). 60 mg (1 grain) are available in bottles of 100 (NDC 0456-0459-01) and unit dose cartons of 100 (NDC 0456-0459-63). 90 mg (1 1/2 grain) are available in bottles of 100 (NDC 0456-0460-01). 120 mg (2 grain) are available in bottles of 100 (NDC 0456-0461-01) and unit dose cartons of 100 (NDC 0456-0461-63). 180 mg (3 grain) are available in bottles of 100 (NDC 0456-0462-01). 240 mg (4 grain) are available in bottles of 100 (NDC 0456-0463-01). 300 mg (5 grain) are available in bottles of 100 (NDC 0456-0464-01). The bottles of 100 are special dispensing bottles with child-resistant closures. Armour Thyroid (thyroid tablets, USP) are evenly colored, light tan, round tablets, with convex surfaces. The ¼ grain strength has: One side debossed with a mortar and pestle beneath the letter “A” on the top and TC on the bottom (NDC 0456-0457-01); or One side debossed with a mortar and pestle beneath the letter “A” and the opposite side debossed with TC (NDC 0456-1045-01). Other tablet strengths have one side debossed with a mortar and pestle beneath the letter “A” on the top and strength code letters on the bottom as defined below Strength Code ½ grain TD 1 grain TE 1 ½ grain TJ 2 grain TF 3 grain TG (bisected) 4 grain TH 5 grain TI (bisected) Note: (T3 liothyronine is approximately four times as potent as T4 levothyroxine on a microgram for microgram basis.) Store in a tight container protected from light and moisture. Store between 15°C and 30°C (59°F and 86°F). *Armour Thyroid (thyroid tablets, USP) has not been approved by FDA as a new drug. Distributed by: AbbVie, Inc., North Chicago, IL 60064 © 2024 AbbVie. All rights reserved. ARMOUR is a trademark of Allergan Sales, LLC, an AbbVie company. Revised: March 2024 20084309 PRINCIPAL DISPLAY PANEL NDC 0456-0457-01 Armour Thyroid (thyroid tablets, USP) ¼ GRAIN (15 mg) Each tablet contains: levothyroxine (T ) 9.5 mcg liothyronine (T ) 2.25 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0458-01 Armour Thyroid (thyroid tablets, USP) ½ GRAIN (30 mg) Each tablet contains: levothyroxine (T ) 19 mcg liothyronine (T ) 4.5 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0459-01 Armour Thyroid (thyroid tablets, USP) 1 GRAIN (60 mg) Each tablet contains: levothyroxine (T ) 38 mcg liothyronine (T ) 9 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0460-01 Armour Thyroid (thyroid tablets, USP) 1½ GRAIN (90 mg) Each tablet contains: levothyroxine (T ) 57 mcg liothyronine (T ) 13.5 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0461-01 Armour Thyroid (thyroid tablets, USP) 2 GRAIN (120 mg) Each tablet contains: levothyroxine (T ) 76 mcg liothyronine (T ) 18 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0462-01 Armour Thyroid (thyroid tablets, USP) 3 GRAIN (180 mg) Each tablet contains: levothyroxine (T ) 114 mcg liothyronine (T ) 27 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0463-01 Armour Thyroid (thyroid tablets, USP) 4 GRAIN (240 mg) Each tablet contains: levothyroxine (T ) 152 mcg liothyronine (T ) 36 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0464-01 Armour Thyroid (thyroid tablets, USP) 5 GRAIN (300 mg) Each tablet contains: levothyroxine (T ) 190 mcg liothyronine (T ) 45 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-1045-01 Armour Thyroid (thyroid tablets, USP) 1/4 GRAIN (15 mg) ARMOUR THYROID ® thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0457 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 15 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 5mm Flavor Imprint Code A;TC Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0457- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-1045 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 15 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 5mm Flavor Imprint Code A;TC Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-1045- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0458 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 30 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 6mm Flavor Imprint Code A;TD Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0458-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0458-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0458-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0459 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 60 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 7mm Flavor Imprint Code A;TE Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0459-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0459-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0459-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0460 Route of Administration ORAL Active Ingredient/Active Moiety Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 90 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 9mm Flavor Imprint Code A;TJ Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0460- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0461 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 120 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 10mm Flavor Imprint Code A;TF Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0461-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0461-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0461-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0462 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 180 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 10mm Flavor Imprint Code A;TG Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0462- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0463 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 240 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 11mm Flavor Imprint Code A;TH Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0463- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0464 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 300 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Allergan, Inc. Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 13mm Flavor Imprint Code A;TI Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0464- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 Labeler - Allergan, Inc. (144796497) Revised: 3/2024

Written by: Hari Krishnan Krishnamurthy , Swarnkumar Reddy, Vasanth Jayaraman, Karthik Krishna, Qi Song, Karenah E. Rajasekaran, Tianhao Wang, Kang Bei and John J. Rajasekaran Vibrant Sciences LLC., San Carlos, CA, USA/Vibrant America LLC., San Carlos, CA, USA Abstract Micronutrients are involved in various vital cellular metabolic processes including thyroid hormone metabolism. This study aimed to investigate the correlation between serum levels of micronutrients and their effects on thyroid parameters. The correlation of serum levels of micronutrients and thyroid markers was studied in a group of 387 healthy individuals tested for thyroid markers (T4, T3, FT4, FT3, TSH, anti-TPO, RT3, and anti-Tg) and their micronutrient profile at Vibrant America Clinical Laboratory. The subjects were rationalized into three groups (deficient, normal, or excess levels of micronutrients), and the levels of their thyroid markers were compared. According to our results, deficiency of vitamin B2, B12, B9 and Vit-D25[OH] (p < 0.05) significantly affected thyroid functioning. Other elemental micronutrients such as calcium, copper, choline, iron, and zinc (p < 0.05) have a significant correlation with serum levels of free T3. Amino acids asparagine ( r  = 0.1765, p < 0.001) and serine ( r  = 0.1186, p < 0.05) were found to have a strong positive correlation with TSH. Valine, leucine, and arginine (p < 0.05) also exhibited a significant positive correlation with serum levels of T4 and FT4. No other significant correlations were observed with other micronutrients. Our study suggests strong evidence for the association of the levels of micronutrients with thyroid markers with a special note on the effect of serum levels of certain amino acids. 1. Introduction The deficiency of micronutrients such as vitamins and minerals is of great concern in public health. The World Health Organization (WHO) reported more than 2 billion people are affected by micronutrient deficiency and its related health consequences [ 1 ]. Iodine, iron, vitamin A, and zinc are the primary micronutrients that have been the focus of development efforts since they have major health implications. Micronutrient deficiency is regarded as a preventable cause of various nonspecific physiological impartments such as suppressed immune responses, metabolic disorders, and delayed or impaired physical and psychomotor development [ 2 ]. Elimination of micronutrient deficiencies through nutrition supplementation programs is widely seen as the most promising and cost-effective way to eradicate nutrition deficiency. The optimal metabolic functioning of an individual requires a proper supply of micronutrients such as vitamins, coenzymes, and intracellular elements. Micronutrients play a crucial role in catalyzing various enzymatic reactions, regulating the permeability of cell membranes, and various other physiological activities [ 3 ]. Nutritional alterations result in various endocrine dysfunctions with a prime effect on thyroid functioning. Thyroid disorders are the most common endocrine disorders and are known to affect 5% to 6% of the US population. Thyroid hormone is a sensitive hormone and synthesized by an autoregulated feedback loop mechanism regulated by the hypothalamus-pituitary-thyroid (HPT) axis. Thyroid hormones are involved in various developmental and physiological functioning. Regular functioning of a thyroid gland is characterized by the synthesis of the appropriate amount of triiodothyronine (T3) and thyroxine (T4) in response to thyroid-stimulating hormone (TSH) synthesized by the pituitary gland. Any physiological or biochemical alterations in the feedback loop result in thyroid dysfunctions and result in catastrophic health consequences. These alterations may arise from several pathologies; autoimmune disorders are the most common cause of thyroid disorders which results in excess (hyperthyroidism) or diminished (hypothyroidism) levels of thyroid hormones. Other reasons may include various environmental factors and demographic and intrinsic factors [ 4 ]. Autoimmune responses, thyroid surgery, radiation therapy, congenital hypothyroidism, etc. are the most commonly studied factors of thyroid dysfunctions. The pathogenesis of thyroid disorders has also been shown to be highly influenced by dietary factors, i.e., the availability of micronutrients such as iodine, vitamin D, iron, selenium, copper, zinc, vitamin B12, etc. Micronutrients are involved in physiological functioning like hormone synthesis, hormone transportation, and its binding to a target receptor. Micronutrients also play a pivotal role in regulating autoimmune thyroid disorders (AITD). Hypothyroidism is an autoimmune thyroid disorder resulting from iodine deficiency. The synthesis of both thyroid hormones triiodothyronine (T3) and thyroxine (T4) is inhibited by iodine deficiency which in turn induces the autoantibodies against the thyroid gland and results in goiter [ 3 ]. Hashimoto’s thyroiditis (HT) is an autoimmune disorder characterized by hypothyroid functioning resulting from vitamin D deficiency. In addition to these nutrients, several other micronutrients such as amino acids, cofactors, and metal ions are essential for thyroid functioning. But only a few studies have reported the marginal possibilities of these micronutrients in altering thyroid functions. The present study is designed to evaluate the significant correlation between the serum levels of vital micronutrients and thyroid function. 2. Materials and Methods 2.1. Subjects and Study Design The study population comprised 387 individuals aged between 13 and 85 subjects who were tested for various thyroid markers (thyroxine (T4), triiodothyronine (T3), free T4 hormone (FT4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), antithyroid peroxidase (anti-TPO), reverse T3 (RT3), and antithyroglobulin (anti-Tg)) and micronutrient panel at Vibrant America Clinical Laboratory. The female to male ratio was 2 : 1 (69% female, 31% male), and the mean age (±SD) of the subjects was 48 ± 16 years. The study was exempted from formal ethical reviews by Western IRB (Washington, USA) since the study comprises the retrospective analysis of deidentified clinical data and test results. The subjects were categorized on the serum levels of thyroid markers listed in Table 1 . 2.2. Reference Range of Thyroid Markers and Micronutrients The reference ranges of thyroid markers and micronutrients tested depend on the lab where the test is performed. The present study followed the reference ranges widely followed by commercial diagnostic labs and hospital labs. The reference range of thyroid hormones and autoantibodies is shown in Table 1 . The optimum serum levels of essential micronutrients are provided in Table S1 . 2.3. Serum Analysis Serum levels of TSH, FT4, anti-TPO, and anti-Tg tests were measured using a commercial Roche e601 analyzer (Roche Diagnostics, Indianapolis, IN, USA) following the manufacturer’s instructions. All reagents were procured from Roche Diagnostics (Indianapolis, IN, USA). Monoclonal antibodies specifically directed against human TSH were employed for the Elecsys TSH assay. The presence of chimeric construct from human- and mouse-specific components in antibodies labeled with ruthenium complex results in the elimination of interfering effects of HAMA (human anti-mouse antibodies). For the Elecsys T4 and FT4 test, a specific anti-T4 antibody labeled with a ruthenium complex was used for the determination of free thyroxine. The use of a small quantity of the antibodies (equivalent to approx. 1-2% of the total T4 content of a normal serum sample) enables the equilibrium between bound and free T4 virtually unaffected. Serum levels of free triiodothyronine and bound triiodothyronine were determined using Elecsys FT3 assay, a specific anti-T3 antibody with a ruthenium complex. Human antigen and monoclonal human anti-Tg antibodies were employed for the Elecsys anti-Tg assay whereas Elecsys anti-TPO assay used recombinant antigens and polyclonal anti-TPO antibodies for the determination of serum levels of anti-TPO. Serum levels of RT3 were determined by a sensitive and reliable LC-MS/MS technique. Analytical standards of thyroid hormones were procured from Cerilliant Corporation (Round Rock, Texas), and the serum samples were analyzed using Waters TQ-S Tandem Mass Spectrometer. Serum levels of micronutrients were analyzed using Waters TQ-XS Tandem mass spectrometer (LC-MS MS), Waters GC-MS, and Perkin Elmer NexION ICP-MS using standard protocols. 2.4. Statistical Analysis The processing of clinical data from deidentified subjects was performed via Java for windows version 1.8.161, and statistical analysis was performed using GraphPad Prism version 7.00 (Windows). Descriptive statistics were used to define continuous variables (mean ± SD, and median, minimum and maximum) with statistical significance set at p < 0.05. Mann–Whitney U test was used to compare two independent groups without normal distribution, and this method offers the advantage of possible comparison of small samples of subjects. Univariate relationships between variables were analyzed using Pearson’s correlation analysis with significance set at p < 0.05. 3. Results The present study aimed to evaluate the significance of 37 micronutrients on selected thyroid parameters. The study was conducted on the general population without any clinical prevalence of thyroid disorders. The mean age of the candidates involved in the study was 44 ± 14.5, and the study includes 70% females (Table 1 ). The subjects were categorized into three groups based on the serum concentrations of micronutrients being less than the reference range, within the reference range, and higher than the reference. The analysis showed a significant relationship of selected micronutrients on the expression of thyroid hormones; decreased levels of amino acids such as asparagine, glutamine, serine, valine, citrulline, and arginine had a significant effect on thyroid parameters. Deficiency in these amino acids significantly alters the thyroid functioning, specifically, the deficiency of citrulline increased the serum levels of T4 (p < 0.001), and low levels of arginine decreased the serum levels of T3 (<0.0001). Thyroid functions were significantly affected by the various vitamin deficiencies; the present study observed that Vit B2, Vit B12, Vit B9(Folate), and Vit-D25[OH] are the most significant for normal thyroid functioning. Serum levels of T4 were significantly lower in subjects with low Vit B2 (p < 0.01). Vitamin B9 (folate) deficiency is the most significant factor affecting thyroid functioning as it increases the serum TSH level (p < 0.01), increases anti-TPO levels (p < 0.05), and also elevates the serum levels of anti-Tg (p < 0.001). Apart from amino acids and vitamins, other micronutrients such as calcium, copper, chromium, selenium, inositol, and carnitine have significance on thyroid functioning. Decreased serum levels of carnitine were characterized by a significant increase in the levels of anti-TPO levels (p < 0.001) and anti-Tg (p < 0.01). While low levels of micronutrients are a concern, high levels can also result in adverse effects. Elevated levels of inositol and copper beyond the reference range have a significant increase in the serum levels of T4 and T3 (p < 0.001). Increased levels of selenium also show considerable significance in decreasing the levels of T3 and Free T3 (p < 0.01) (Table 2 ).