Søkeresultater

The Chinese used burnt sponge and seaweed to treat goiter 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 century , from Switzerland   Albrecht Von Haller in the 18th century and British Thomas Wilkinson King who was a physiologist in the early 19th century , each wondered whether the thyroid elaborated a secretion which was carried away by the veins. In 1786 , Caleb Hillier Parry recorded the first case of Parry’s disease, a malady ‘ which had not been noticed by medical writers ’. Parry certainly noticed it, describing it as an ‘ Enlargement of the Thyroid Gland with Enlargement or Palpitation of the Heart .’ He was thr first to describe exophthalmic goiter. 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. 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 , it was John Elliotson from St Thomas’ Hospital who used it for goitre in 1819 . 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 . 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 Jean-Baptiste Boussingault used iodised salt in present day Columbia for the same condition. In 1835 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”, since known as Graves’ disease, although as we know today, this condition was first described by Caleb Hillier Parry in 1786. 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. John Simon published his first article on the neck ( 1842 ). Two years later in 1844 he won a financial prize for a physiological essay on the thymus gland. Following another paper on the comparative anatomy of the thyroid. He confirmed the 17th century theory of Frederik Ruysch. In 1850 , Thomas Blizzard Curling correlated the absence of thyroid tissue at autopsy in two children with cretinism. 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 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. 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. In 1871 , Charles Hilton Fagge presented a paper describing four children with sporadic cretinism and wondered whether the thyroid had ‘wasted’. 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. He described hypothyroidism in adult life as creating a cretinoid appearance with a thick tongue. They were slow, sluggish, obese and puffy in the face. 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. 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. 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. Also in 1883 , the Committee of the Clinical Society of London set it upon itself to investigate the cause of myxoedema. Five years later the Committee announced its verdict: myxoedema was caused by thyroid deficiency. Much of the evidence for that bold statement was based on simple clinical observation.  For instance, Theodor Kocher (1841-1917), an eminent Swiss surgeon who perfected the art of thyroidectomy, noted that some of his patients who had total thyroidectomies, subsequently developed the typical features of myxoedema. Following the announcement of the Committee of the Clinical Society of London, progress was rapid even with today’s standards. Ivar Sandstrőm , Uppsala medical student in 1887 , confirmed the existence of the parathyroid glands in 50 autopsies. 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. Reporting in 1888 and using experimental work on thyroidectomised monkeys by Sir Victor Horsley, 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. Up until 1891 : Before a treatment was discovered and became routine, hypothyroidism could progress to severe myxedema: advanced hypothyroidism characterized by swelling, depressed breathing and low oxygen levels, mental slowness, and seizures. Myxedema was usually fatal, typically taking about 10 years from the diagnosis of myxedema to coma, and eventually, death from respiratory and heart failure. In 1891 , Horsely and Professor George Redmayne Murray 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. 1891 :  First recorded use of thyroid extract in the US. Thyroid extract was not a mass produced drug. Instead, it was produced by apothecaries, also known as chemists or druggists, who custom-prepared medications. In 1892 Edward Fox showed that thyroid extract did not have to be injected, it worked just as well when taken by mouth. From that point onwards the standard remedy from myxoedema became “half a sheep’s thyroid, lightly fried and taken with currant jelly once a week”, and so oral replacement therapy for glandular hypofunction was born. In 1893 , 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. In 1894 the pharmaceutical company Merck started producing commercial quantities of thyroid extract and “Thyroidinum siccatum” (desiccated thyroid) became widely available and could be prescribed until the 1980’s. 1894 : Thyroidinum siccatum   Introduction of desiccated sheep thyroid gland (powder, later tablets) in Germany. Available as Thyroidin Merck until 1983. 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. 1896 : Thyroidin Merck  (USA) Offered in the price list published in Merck's 1896 Index (New York). Early 1900s :  The Armour Meat Packing company made Armour Thyroid available to apothecaries as an ingredient for thyroid extract In 1901 , the French physiologist Eugene Gley   linked the absence of parathyroids after thyroid surgery to tetany which was often a sequel. 1901 : Antithyroidin Merck Produced from the serum of thyroidectomized rams (Moebius). In 1905 , Ernest Starling proposed that the substances they worked with 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. 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. 1911 : Glandula Thyroideae siccata "Merck" Tabletten   Dessiccated thyroid gland available as tablets. 1912 : Research on a standardized thyroid extract product (Annual report Scientific Laboratory 1912). 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. 1920 :  Dr. George Redmayne Murray published a description of a patient successfully treated for almost 30 years with thyroid extract. 1921 : Thyreoidinum depurat. Notkin Tabletten Thyroid protein extract. 1925 : Evaluation of Kendall's Thyroxine   "Obviously thyroxine is not the only active thyroid product". 1925 : Thyroidea Opton Introduction of protein-free degradation product of the thyroid gland. In 1927 the chemical structure of thyroxine was discovered. 1928 : Novothyral   Introduction of water soluble standardized thyroid extract (Axolotl). 1934 :  Western Research Laboratories was founded by Dr. William McClymonds to manufacture and distribute the first commercially-prepared and distributed natural desiccated thyroid drug, called Westhroid. 1938 : The new federal Food, Drug and Cosmetic Act gave the Food and Drug Administration (FDA) oversight over various medications, and established formalized approval processes. As an existing medication, natural desiccated thyroid was “grandfathered,” and not required to go through any approvals. Broda Barnes' study of over 70,000 of these autopsy reports spanning the war years of 1939-1945 , lead Barnes to conclude that atherosclerosis, the underlying cause of heart disease and heart attacks, was not caused by diet and cholesterol as is widely believed, but instead by hypothyroidism. 1941 :  Thyroidin Merck   Standardized also with Axolotl method. 1942: Broda Barnes' "Barnes Basal Temperature Test" was published in the Journal of the American Medical Association (JAMA). 1948 : Methicil   Brand of Methylthiouracil available from Merck in Germany. 1949 :  Levothyroxine (synthetic thyroxine) became commercially available. New drug application and approval was not required by the FDA at that time. 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). NDT is slowly starting to being phased out. 1960 : The first commercial tests to measure thyroxine became available. They measured total thyroxine (TT4). Before this, a convenient measurement of thyroid hormones was not possible. Until this year, clinical assessments and patients' symptoms were dominant in diagnoses of various degrees of hypothyroidism. However, breakthrough though this was, it was immediately realised that this was insufficient for accurate estimation of thyroid function. Thyroid hormones (T4 and T3) leave the thyroid gland and in the bloodstream are bound onto transport proteins that convey the hormones to the tissues. There are three of these transport proteins: thyroxine-binding globulin (TBG), transthyretin and albumin. Of these, TBG is the most important in the average person. It transports about 70% of T4 and 60% of T3. As the transport proteins and their T4/T3 load pass by the tissues in the bloodstream, very small amounts of hormone are freed as required. These are the free T4 and free T3 fractions. As the tissues remove T4 and T3 for their own use, more is released by the transport proteins for the next tissues to use. The free T4 (FT4) and free T3 (FT3) fractions are a very small percentage of the total circulating hormones. In the case of FT4 in the average person it is about 2/100 of 1% of the total T4 and for FT3 2/10 of 1% of the total T3. Therefore, it is necessary to measure FT4 and FT3 rather than total T4 or total T3. The problem is that we are all unique in the makeup and amounts of our transport proteins. In the vast majority of people, the TBG levels can be different by at least a factor of 2; and the same (independently) for the other two proteins. There are people with either no TBG at all or 4 times the normal amount. Their reservoirs of T4 and T3 are therefore hugely different for the same FT4 and FT3. Also, the pregnant woman has twice the TBG and ¾ the amount of albumin she had when not pregnant. We also lose transthyretin and albumin when critically ill or with trauma like burns or septicaemia. To try to get a measure of FT4, a test was developed in 1963-65 to try to convert the total T4 result to a FT4 result. This was the thyroid hormone uptake test . In conjunction with a total T4 result, the two tests could be amalgamated to produce what was claimed was an estimate of FT4. This thyroid testing method is still used today; e.g. in certain American private labs and elsewhere. However, it is not based on sound principles and does not work properly, especially for people with extreme differences in TBG from the average. Even the pregnant woman’s results are compromised. In the remainder of the 1960s, commercial firms were set up to provide readymade tests for the clinical chemistry labs to use By the 1960s , synthetic T4 and T3 could be made. Desiccated thyroid however remained in use as synthetic thyroid hormones were expensive to manufacture. 1960s–1990s : Levothyroxine increasingly replaced the use of natural desiccated thyroid in the UK and US. 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. 1965 : Kalium jodatum Compretten (100 mg KI) Indicated for prevention of radioactive iodine incorporporation in nuclear accidents. 1966 : A peak of 16.6 million prescriptions filled for NDT 1968 : Novothyral   Newly introduced as a T4/T3 combination in Germany. The next landmark in the history of thyroid hormones was the discovery by Dr L Braverman in 1970 that most of the active thyroid hormone T3 was made by tissues such as the liver from thyroxine secreted by the thyroid gland. This discovery formed the basis for the concept that although the tissues in the body only “see” T3, patients with hypothyroidism can be treated with T4 alone. 1970 :  Armour and Company acquired by bus company Greyhound Corporation. From the 1970s onwards synthetic T4 could be manufactured cheaply and it replaced the earlier regimens which contained both T3 and T4. In the 1970’s and 1980’s there was also a universal tendency for the replacement dose of thyroxine to be reduced. Whereas T4 doses in the 1970’s of 300 micrograms per day or more were standard, few patients nowadays are treated with more than 150-200 micrograms of T4 daily. The trend for using lower doses of thyroxine originated from the introduction of sensitive blood tests to monitor thyroxine treatment and the demonstration that the traditionally higher T4 doses resulted in suppressed serum TSH and elevated T4 levels in blood. In many cases features of hyperthyroidism were associated with such treatment. 1973 : Euthyrox   Mono T4 tablets introduced in Germany, later in many other countries. 1975 : Jodid Merck   Iodide 100 µg tablets (later 200 and 500 µg) introduced in Germany. 1975 : The first commercial tests for TSH and T3 hit the market. A few years later, tests for FT3 arrive. The TSH test was the first generation – that is, it could only measure and detect hypothyroidism  (the depressed levels in hyperthyroidism  were too low to be measured directly). 1978 : Greyhound sold Armour (Pharmaceuticals division) to Revlon. In the late 1970s the shortcomings of the thyroid hormone uptake test, arising from the variation in TBG levels in patients, were very apparent. The demand for properly formulated and soundly developed FT4 and FT3 tests was very great. As a response, companies and individuals produced various forms of thyroid testing claiming to measure these fractions. Many of the offerings were not soundly based, and slowly disappeared into obscurity and obsolescence. Two methods did however prevail and form the basis of FT4 and FT3 testing today. In the 1980's , Broda Barnes estimated that the prevalence of undiagnosed hypothyroidism had risen to affect more than 40% of the American population. 1981 : Dennis Jones/Jones Medical Industries (JMI) acquired Western Research Laboratories from the McClymonds family. 1982 :  Nature-Throid -- a hypoallergenic version of Westhroid -- was released by Western Research. In the mid 80s , pressures on the clinical chemistry lab were beginning to be overwhelming. Such was the demand for tests that the disposal of radioactive waste was too great for licencing of disposal. Consequently, non-radioactive detection methods had to be substituted. Two things happened around 1985 . First , second and third-generation TSH tests were developed – now one could directly detect both hypo and hyperthyroidism. Secondly , the manufacturers produced several solutions to the non-radioactive detection methods and integrated them into dedicated automatic analytical platforms. Now one had machines that took the place of the skilled hands-on technician – it was a case now of loading the machine, programming it and pressing the “start” button. This led to lab monopoly – having chosen the machine, one was confined to the tests dedicated to that machine. However, the individual solutions of the manufacturers to the method of detection in tests led to problems with FT4 and FT3 test development (uniquely). Unlike all other tests, FT4 and FT3 tests demand special and essential requirements. They must be run at blood temperature (37 degrees), they must sample only a tiny quantity of the available T4 and T3 so as not to sample the T4 and T3 bound to the transport proteins, they must use the same chemical surroundings (for example, salt content, phosphate content) as is present in the blood, and they must work in the right acidity as present in the blood. The failure of the development scientists to understand these special requirements, and the compromises needed to make the detection methods work, led to great variation in the performance of the FT4 and especially the FT3 tests between manufacturers offerings. For FT4 this is at present up to 40% difference and for FT3 60%. One would expect no more than a 5% difference as a reasonable variation. As a result, sensitive TSH tests began to have a paramount position in thyroid function testing. There exists a paradigm of thinking today which closely links FT4 and TSH as a constant relationship over the whole thyroid function spectrum. Therefore, if you do a TSH test, then why do an FT4 test because the TSH value implies an FT4 value – the FT4 test is controversial and inconsistent so why do it? The seeds of TSH only screening had started to sprout. 1985 : Revlon sold its drug unit – including Armour Thyroid -- in 1985 to Rorer (later known as Rhône-Poulenc Rorer). 1985 : Jodthyrox   T4/Iodide combination introduced in Germany for iodine deficiency goiter. 1988 :  4.5 million prescriptions filled for NDT -- Armour Thyroid, Westhroid, and Nature-Throid. In 1988 , John Midgley and his colleagues invented a new test for FT4 and FT3, based on the invention of 1980 but getting rid of the problems at the margins mentioned earlier. 1990 : Thyrozol   Thiamazole (Methimazole) introduced in Germany. 1990 - 1997 : The FDA reported 10 recalls of levothyroxine , covering 150 different lots of medication, and a total of 100 million tablets. 1991 :  Forest Laboratories acquired the rights to Armour Thyroid from Rhône-Poulenc Rorer In 1992 , a group of American scientists had begun to analyse and dissect the commercial FT4 tests to understand why they were so inconsistent. They began a series of papers in the peer-reviewed important leading journals which lasted until 2009 . Their findings were on the surface devastating – that is, they alleged that however it came about, all FT4 tests were influenced by the levels of transport proteins in the blood – devastating because this meant that they were subject to the T4 and T3 bound by those transport proteins – and the whole point of doing FT4 and FT3 tests is to be independent of these effects. As it turned out, the whole of this work was completely invalid and wrongly conceived from beginning to end – a completely meaningless study programme. John Midgley and a colleague pointed this out but, especially in America, their findings are accepted and further confuse today’s understanding of the FT4 and FT3 tests. Meanwhile, the cheap, easy to understand, rapid, and eminently automatable TSH test was gaining strength as a catch-all screen. 1993 : Beginning globalization of Merck KGaA's thyroid business. 1997 :  With 37 different manufacturers and repackagers of levothyroxine on the market, and widespread and ongoing problems with content uniformity, sub-potency, and stability, the FDA launched an effort to standardize levothyroxine sodium tablets, and to minimize potency fluctuations. As a result, the FDA declared levothyroxine sodium tablets a “new drug,” and required new drug applications for approval of all levothyroxine drugs. (NDT was not included in this FDA ruling, and remained grandfathered.) 1998 :  Western Research Laboratories was acquired by the Cox family: Rick, Judy, Lindsay and Riki Cox. In 1999 Bunevicius and colleagues published a study of patients who were given T4 and T3 in combination and were compared with patients who received T4 alone. They found that patients on T4 and T3 felt and performed psychologically better. 1999 – 2001 :  Several companies submitted NDAs for levothyroxine, and the first product (Unithroid) was approved in August of 2000 . Synthroid filed a citizen's petition to bypass the NDA process, but that was rejected by the FDA, and an NDA was ultimately filed for Synthroid. The same scientists did another study in 2002 , but were unable to confirm their earlier findings. Since then, another five studies exploring the same theme were conducted in various corners of the word. The findings were equally disappointing. No difference between T4 alone and combination of T4 with T3 (although a “placebo” effect was frequently observed). In some of the studies the combination treatment fared worse that T4 alone. The difficulty with all of the above studies is that it is still impossible to reproduce what the normal thyroid does with T4 and T3. In particular T3 has “a short half life”, i.e. after a dose of T3 is taken there is a rapid rise followed by a rapid fall in blood levels. Could these ups and downs be negating the potential benefits of T3 and even be responsible for the observation that in some studies combination was worse that T4 alone? It is possible. What one should use ideally is a slow-release preparation of T3 that provides a similar profile to the normal situation. Sadly, despite the enormous advances in pharmaceutical science and the availability of numerous drugs in “slow-release” preparations, no such alternative exists for T3. On several occasions there have been attempts, but every signle one has failed to stimulate any interest by the pharmaceutical industry in this, although it is technically feasible and potentially profitable if it proves to be effective in the treatment of hypothyroidism. Another reason why the T4 and T3 combination treatment story is not over, is that the ratio of these substances (i.e. relative doses) should be as close to what the normal thyroid produces as possible and not all of the above studies addressed this important issue. In 2005 a new group of US workers came on the scene with a specialised technique for measuring FT4 and FT3 which they alleged was superior to the commercial thyroid testing in that it more closely correlated FT4 and TSH. In 2009, John Midgley looked into their work and found it had been done at the wrong temperature – this is important because T4/T3 binding to TBG is very temperature sensitive. On advising them of this, they merely obfuscated and blustered, and though henceforward using the right temperature, did not retract their earlier wrong work but actually included it in papers when they used the right temperature as if the wrong work somehow backed them up. 2006 :  The name of Western Research Laboratories was changed to RLC Laboratories. 2013 : A major study from Walter Reed National Military Medical Center found that 49% of patients preferred natural desiccated thyroid, compared to 18% who preferred levothyroxine, and 33% had no preference. That study also found that patients who preferred natural desiccated thyroid had improved general well-being, significant improvement in thyroid symptoms, and lost approximately 4 pounds, compared to no weight loss or improvements in well-being and symptoms in the levothyroxine group. 2013 :  Acella introduced NP Thyroid as a generic natural desiccated thyroid drug. 2013 :  WP Thyroid was released. ​ 2014 : A study published in the J ournal of Endocrinology, Diabetes & Obesity  found that among patients who didn’t feel well on levothyroxine, 78% who switched to natural desiccated thyroid said they preferred it. ​ 2014-2015 :  Armour Thyroid became an Allergan product with the merger of Forest Laboratories into Allergan. 2017 : Natural desiccated thyroid was the 130th most prescribed medication in the United States with around 5.5 million prescriptions per year (levothyroxine was the 3rd most prescribed drug, with almost 102 million prescriptions and refills). ​ 2018 :  An American Thyroid Association survey of more than 12,000 people with hypothyroidism, found that about 30% of patients take natural desiccated thyroid. The same survey found that patients had a higher level of satisfaction taking natural desiccated thyroid compared to levothyroxine. ​ 2020 :  Pharmaceutical company AbbVie acquires Allergan, including Armour Thyroid.

Found at https://pubmed.ncbi.nlm.nih.gov/15253676/ By Alan R Gaby Abstract Evidence is presented that many people have hypothyroidism undetected by conventional laboratory thyroid-function tests, and cases are reported to support the empirical use of Armour thyroid. Clinical evaluation can identify individuals with sub-laboratory hypothyroidism who are likely to benefit from thyroid-replacement therapy. In a significant proportion of cases, treatment with thyroid hormone has resulted in marked improvement in chronic symptoms that had failed to respond to a wide array of conventional and alternative treatments. In some cases, treatment with desiccated thyroid has produced better clinical results than levothyroxine. Research supporting the existence of sub-laboratory hypothyroidism is reviewed, and the author's clinical approach to the diagnosis and treatment of this condition is described. "Objections to the Use of Armour Thyroid The main objections voiced in textbooks and editorials 1,73 regarding the use of desiccated thyroid are: (1) its potency varies from batch to batch, and (2) the use of T3-containing preparations causes the serum T3 concentration to rise to supraphysiological levels. Regarding between-batch variability, there may have been some problems with quality control a half-century or more ago, and in a 1980 study a number of generic versions of desiccated thyroid were still found to be unreliable in their potency. The amounts of T4 and T3 in Armour thyroid, on the other hand, were found to be constant.74 Moreover, two-year old tablets of Armour thyroid contained similar amounts of T4 and T3 as did fresh tablets. Three studies are typically cited to support the contention that T3 containing preparations should not be used. Smith et al reported a levothyroxine-plus-T3 product caused adverse side effects in 46 percent of patients; whereas, side effects occurred in only 10 percent of those receiving levothyroxine alone.75 In that study, however, the combination product and the levothyroxine product differed substantially in potency. For the combination treatment, each 100 mcg of levothyroxine was replaced by 80 mcg of levothyroxine plus 20 mcg of T3. Considering 20mcg of T3 is equivalent to 80 mcg of levothyroxine, the total hormone dose in the combination product was 60-percent greater than that in the levothyroxine preparation. Therefore, the high incidence of adverse side effects may not have been due to the T3, but to the higher total dose of thyroid hormones. In the second study, by Surks et al, the administration of T3-containing preparations to hypothyroid patients caused the plasma T3 concentration to become markedly elevated for several hours after ingestion of the medication.76 In most cases, however, the amount of T3 administered (50-75 mcg) was considerably greater than that contained in a typical dose of desiccated thyroid (9 mcg T3 per 60 mg),77 and/or the total dose of thyroid hormones given was excessive (180 mcg of levothyroxine plus 45 mcg of T3). By contrast, in a patient given 60 mg of desiccated thyroid, the plasma T3 concentration increased from a hypothyroid level to a euthyroid level. Of two hypothyroid patients treated with 120 mg per day of desiccated thyroid, one showed a relatively constant plasma concentration of T3. In the other patient, the T3 level increased by a maximum of 80 percent, to the bottom of the range seen in hyperthyroid patients, and returned to the baseline value within 24 hours. In that patient, the pre-dose plasma T3 concentration was near the top of the normal range, suggesting that this patient may have been receiving too high a dose of desiccated thyroid. Finally, Jackson and Cobb reported that the serum T3 concentration (measured 2-5 hours after a dose) was above normal in most patients receiving desiccated thyroid.2 They concluded there is little use for desiccated thyroid in clinical medicine. Most of the patients (87.5%) in that study, however, were taking a relatively large dose of desiccated thyroid (120-180 mg daily). Moreover, 57.5 percent of the patients were not being treated for hypothyroidism, but rather to suppress the thyroid gland.  Nearly half of the patients continued to have an elevated serum T3 concentration after they were switched to levothyroxine, even though the equivalent dose was reduced in 62.5 percent of patients. Thus, the elevated serum T3 concentrations found in this study can be explained in large part by the high doses used and by the selection of patients, the majority of whom were not hypothyroid.  What this study does suggest is that desiccated thyroid should not be used for thyroid-suppression therapy. Although the oral administration of T3 causes a transient increase in serum T3 concentrations, that fact does not appear to be of significance for hypothyroid patients receiving usual replacement doses of Armour thyroid. In this author's experience, reports of post-dose symptoms of hyperthyroidism are extremely rare, even among patients taking larger doses of desiccated thyroid. An occasional patient reports feeling better when he or she takes Armour thyroid in two divided doses daily. The nature of that improvement, however, is usually an increase in effectiveness, rather than a reduction in side effects. For patients taking relatively large amounts of desiccated thyroid (such as 120 mg daily or more), splitting the daily dose would obviate any potential concern about transient elevations of T3 levels. In practice, however, splitting the daily dose is rarely necessary."

Collected from Merck's websites https://www.merckgroup.com/en/company/history/the-living-memory-of-merck/organ-therapy.html In 1894, Emanuel August Merck introduced one of the first thyroid preparations in the world. Since then, E. Merck has played a substantial role in thyroid research and development: 1894 : Thyroidinum siccatum Introduction of desiccated sheep thyroid gland (powder, later tablets) in Germany. Available as Thyroidin Merck until 1983. 1896 : Thyroidin Merck (USA) Offered in the price list published in Merck's 1896 Index (New York). 1901 : Antithyroidin Merck Produced from the serum of thyroidectomized rams (Moebius). 1911 : Glandula Thyroideae siccata "Merck" Tabletten Dessiccated thyroid gland available as tablets. 1912 : Research on a standardized thyroid extract product (Annual report Scientific Laboratory 1912). 1921 : Thyreoidinum depurat. Notkin Tabletten Thyroid protein extract. 1925 : Evaluation of Kendall's Thyroxine "Obviously thyroxine is not the only active thyroid product". 1925 : Thyroidea Opton Introduction of protein-free degradation product of the thyroid gland. 1928 : Novothyral Introduction of water soluble standardized thyroid extract (Axolotl). 1941 : Thyroidin Merck Standardized also with Axolotl method. 1948 : Methicil Brand of Methylthiouracil available from Merck in Germany. 1965 : Kalium jodatum Compretten (100 mg KI) Indicated for prevention of radioactive iodine incorporporation in nuclear accidents. 1968 : Novothyral Newly introduced as a T4/T3 combination in Germany. 1973 : Euthyrox Mono T4 tablets introduced in Germany, later in many other countries. 1975 : Jodid Merck Iodide 100 µg tablets (later 200 and 500 µg) introduced in Germany. 1985 : Jodthyrox T4/Iodide combination introduced in Germany for iodine deficiency goiter. 1990 : Thyrozol Thiamazole (Methimazole) introduced in Germany. 1993 : Beginning globalization of Merck KGaA's thyroid business. Help for the thyroid gland in the 19th century In the last quarter of the 19th century, a Swiss surgeon swears by radical removal of the thyroid in severe cases of goiter. Physical and mental limitations were potential consequences of treatment. Preserving residual glandular tissue in the patient is an initial attempt at a solution. In the early 1890s, research scientists all over Europe advocate internal administration of animal thyroid. Suggested delivery forms include extracts and "material delivered raw with some seasoning or cooked in various ways". The age of modern organ therapy has dawned. The notion of curing human illnesses with animal organs has been around since antiquity, but the question regarding the mechanism of action is now being reframed in an entirely new way. "E. Merck’s Annual Pharmacy Reviews" dating from 1896 points out the revolutionary nature of current developments: Although the customary use of organs may have been successful in many cases, it was "not rational". Moreover, the "compound-bound" mechanism of action has already been noted: "Not the organs as such should be used, but their secretions (…). Regrettably, our knowledge (…) is very limited to date." The first Merck thyroid product comes onto the market in 1894. Freshly slaughtered sheep thyroid is dried, powdered and also made into tablets. With "Thyreoidinum siccatum", the company hopes to overcome patients’ reluctance to use other dosage forms. Merck applies the latest scientific insights to develop a product. The highest standards of quality, both with respect to the raw material and its processing, are essential to the product’s efficacy. A dedicated manufacturing facility is built and "every conceivable precaution is observed" to stop the ever so precarious starting material from becoming infected. Research in the following decades is driven by two phenomena: a growing understanding of thyroid gland function, and standardization and checking active ingredient quantity. The research scientists are struck by the variety of symptoms that respond to thyroid medicinal products but do not know the precise mechanism of action. This makes it impossible to isolate specifically effective substances in a chemically pure state and determine their therapeutic value "with clinical accuracy". Standardization is by the biological route. Only in the late 1960s and early 1970s do medicines based on purified thyroid hormone preparations usher in a new era in thyroid disease management. The first Merck thyroid products enter the market in 1894. The packaging is from a later date. "E. Merck's Annual Pharmacy Reviews", 1894, states that the whole thyroid is used for the purpose, since it was not known for sure "to which component (...) the specific effect is attributable." Production records are available since 1895. The importance of the organ products business grows. A new building is erected in 1935 in the southern part of the company premises on Frankfurter Strasse. The employee newpaper comments: "The size and features of this production unit indicate that the products manufactured here must be of significant importance." New products are also launched on the basis of collaboration with external scientists. A clear theoretical underpinning of the clear therapeutic success is still lacking, however. The active ingredient is standardized in the 1930's, one contributor being the axolotl. Organ products are a success, both nationally and internationally.

Written by Lisa Victoria Larsen The endocrine system is in charge of creating and releasing the hormones that is needed to maintain countless bodily functions. The tissues of the endocrine system includes your hypothalamus, pituitary gland, pineal gland, thyroid gland, parathyroid glands, adrenal glands, pancreas and reproductive organs. Hormones are chemicals. They carry instructions through your blood to your organs, skin, muscles and other tissues. There are more than 50 different hormones and they affect almost every aspect of your body. They tell your organs what to do and when to do it. Glands are tissues that create and release substances. They send hormones directly into your bloodstream. The endocrine system controls the metabolism, internal balance (homeostasis), growth, development, reproduction, sleep, mood, energy, digestion, blood sugar, sexual drive, blood pressure, and the nervous system. Metabolism provides energy for essential body functions like breathing, digestion, circulating blood, regulating body temperature and growing and repairing cells. It refers to the chemical processes that happens in your body when you eat, drink, rest, and breathe. The process is complex, regulating conversion of the things you digest to combine calories and oxygen to create and release energy. And it never stops. We have this thing called Basal Metabolic Rate (BMR), which refers to the absolute minimum amount of energy you need to exist. This amount is individual. There is a difference between a fast metabolism and a slow metabolism. People with fast metabolisms burns many calories even while resting. The ones with a slow metabolism needs fewer calories to keep everything going. A fast BMR does not necessarily lead to a thinner body. They just need more energy to maintain their essential body functions. Many factors can weigh in on how well your metabolism works. For instance: - Muscle mass ; People with more muscle mass tend to have faster metabolisms, and it takes more energy to build and upkeep muscle mass than fat. - Age ; When getting older, muscle mass tends to get smaller. This slows down our metabolism. - Gender ; Men usually have faster metabolisms than women because they have more muscle mass, bigger bones and less body fat. Women generally needs more body fat to reproduce. - Genes ; What you inherit from your parents can be a factor when it comes to your ability to build and store muscle mass. - Activity ; Exercise in all forms cause your body to burn more energy than it does resting. This includes walking, sports, raising small kids etc. - Smoking ; One reason people who quit smoking may gain weight is that nicotine speeds up your metabolism. Although it may be very negative for other health issues like cancer, high blood pressure, coronary artery disease. Homeostasis is, in simple terms, a self-regulating process. It involves three mechanisms; a receptor, a control center and an effector. These three work together to keep your body in balance, noticing changes in your body and then starting processes to regulate your system. It refers to any automatic process that anyone needs to stay balanced on the inside, and the body does this to make sure that everything works the right way and we stay alive. It really is quite complex. In a state of homeostasis, your levels are rising and falling as responses to changing enviroments, for instance blood sugar, blood pressure, energy level, acid levels, oxygen, proteins, temperature, hormones and electrolytes. When the system is disturbed, your body will react to create balance again. This can be made possible by the nervous system, the hormonal system or electrical currents. Allostasis is another term that is used to describe our body's ability to foresee, adapt and deal with future events of balance. It really is preparing for needs and managing resources so that your body can adjust before the problems arise. - The receptor of homeostasis; these are cells, tissues and organs that track your system and spots any changes. When the change comes, they notify the control center. - The control centers are often found in the brain, and are the determinators of what is "your normal" and what to do to achieve this. The control center will notify the effector. - The effector is your cells, tissues and organs that then will react to the signals and start the correcting process to achieve the wanted balance. Growth ; three different ways that we grow are through cell count increase, cell mass increase and a rise of non-cellular particles that circles the cell. We grow from birth until death in one way or another. It is a biological process that happens as a result of formation of new cells and packing proteins or other materials into cells that already are there. The growth is not constant in every part of the body, as it is different rates of maturing in different tissues and regions of the body. Human growth hormones (HGH) are produced in your brain's pituitary gland, which controls your height, bone lenght and muscle growth. These hormones increase during childhood and peaks at puberty. Throughout life, the hormones regulates fat, muscle mass, tissue and bones, in addition to insulin and blood sugar levels. These hormones tells your liver to produce a substance called insulin-like growth factor (IGF-1). Acromegaly is a condition that is caused by excess levels of growth hormones, typically as a result of a pituitary tumour. Development ; human organs and organ systems develop in a process called organogenesis. The pituitary gland sends out two hormones concerning development, follicle stimulating hormone (FSH) and luteinizing hormone (LH). These make sure that we develop male or female reproduction abilities. The thyroid is another important gland when it comes to development. Without thyroid hormones, your body's development will not be normal. The thyroid is the body's first endocrine gland to develop in the gestation process. In adults, thyroid hormones can influence mood and behavior. Thyroid dysfunction can affect neurotransmitter systems and lead to psychiatric disorders. Adrenocorticotropic hormone (ACTH) controls the coordinated development of the vasculature and endocrine tissue mass. ACTH is a tropic hormone that indirectly affects target cells by first stimulating other endocrine glands. ACTH stimulates the adrenal glands to produce cortisol, the stress hormone, which again plays a role in glucose metabolism and immune function. Reproduction ; the main hormones of reproduction are estrogen, testosterone and progesterone. They are responsible for puberty, menstruation, menopause, sex drive, sperm production and fetal egg production. They are produced in the female ovaries and male testes. Other hormones that play a part in this are human chorionic gonadotropin (HcG), prolactin, luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are produced, stored and stimulated by the pituitary gland. Estrogen causes eggs to mature in the ovaries when women hits puberty. These are then released during the menstrual cycle. In males, testosterone stimulates sperm production in the testes. In males, the endocrine regulation is as follows: - The hypothalamus releases gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). - FSH and LH travel through your blood and bind to receptors in the testes. - FSH stimulates the production of sperm cells (spermatogenesis). LH stimulates production of testosterone in the testes. - Together, FSH and LH controls the function of the testes. - Your adrenal glands also produce a hormone (DHEA), which your body transforms into testosterone. - Testosterone also signals your body to make new red blood cells, ensures that you bones and muscles stay strong, and enhances libido (the sex drive). In females, the endocrine regulation is as follows: - The hypothalamus releases gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). - FSH and LH travel through your blood and bind to receptors in the ovaries. - FSH and LH promote ovulation and stimulate secretion of estradiol (an estrogen) and progesterone from the ovaries. - Estrogen and progesterone circulate in the bloodstream, almost entirely bound to plasma proteins. Only unbound estrogen and progesterone appears to be biologically active. - They stimulate the uterus, vagina and breasts to prepare for pregnancy. Sleep interacts with the endocrine system over a wide range of hormones. But what is really sleep? It is a state in which the consciousness is lost and motoric function is reduced. It also comprises different stages of brain waves of different patterns, with the most well known being rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. NREM is characterized by orderly synchronized brain activity, with the brain moving from phases of light to deep sleep. Deeper sleep means slower brain waves. While your muscles are relaxed, they are not paralyzed. On the other hand is REM, which occurs after slow-wave sleep is completed. In the REM stage, the brain shows very disorderly brain waves, similar to the awake brain. Skeletal muscles are paralyzed. Sleep is regulated by the circadian system and the sleep pressure system. Sleep pressure is the need to sleep of any organism at a given moment. Both these systems work in parallel and are responsive to the hours in a day and the organism's homeostatic processes. Circadian rhytms are shifted by external cues like light and dark, exercise, food intake, temperature and various chemicals/medicines. The master circadian clock is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN enables the body to sleep in long periods related to external light and dark, which are translated into biological day and night, and also regulates the daily rhythm of hormonal secretion and other biological processes. The sleep pressure system determines how much sleep each person needs to return to the normal state. When it comes to keeping track of the day-night cycle, the SCN helps with the secretion of high cortisol early in the morning, to be ready and alert for the activity of the wake cycle. Several hormones are involved in sleep and our circadian rhythm. Growth hormone levels are increased during deep sleep and are vital for cell growth and repair. Growth hormones in turn, affects the regulation and metabolism of glucose, lipids and proteins. Melatonin levels are high during the biological night versus day. It plays an important role in regulating human sleep patterns. Basically it tells your body when to sleep. Melatonin also controls more than 500 genes in the human body, including the genes involved in the immune system. Thyroid stimulating hormone (TSH) concentrations reach their maximum and minimum in the middle of the biological night and afternoon. T3 and T4 concentrations are not associated with circadian rhytmicity. Mood is affected by almost all of your hormones in one way or another. The hormones that perhaps impacts your mental health more than others are serotonin, dopamine, thyroid hormones and sex hormones. - Serotonin is a chemical that carries messages between nerve cells in the central nervous system in the brain and throughout your body. It's techically a monoamine neurotransmitter known as hydroxytryptamine (5-HT), which also acts as a hormone. Most of the serotonine found in your body is in your gut. Actually, about 90% of it is found in the cells lining your gastrointestinal tract. It's made from the essential amino acid tryptophan. An essential amino acid means it can't be made by your body. It has to be obtained by the food you eat. Serotonin is often called one of the "feelgood" chemicals. When it's at a normal level, you feel more focused, emotionally stable, happier and calmer. Low levels are associated with depression. - Dopamine is also a monoamine neurotransmitter. It plays a role in the "fight-or-flight" response. It also causes blood vessels to relax or constrict. Dopamine increases salt and urine removal from your body, as well as reduces insulin production in the pancreas. Dopamine is another "feelgood" chemical, being a part of your reward system. This system is designed from an evolutionary standpoint, to reward you when doing the things you need to do to survive, like eat, drink, reproduce and overcome obstacles. As humans, we are hard-wired to seek out situations that releases dopamine in our system. It makes us feel good and we seek more of that feeling. This is why junk food and sugar is so addictive. They trigger the release of a large amount of dopamine into your brain and gives a feeling that you want to repeat. Dopamine makes you experience happiness, motivation, alertness and focus. - Thyroid hormones commonly affect your mood, and the more severe the thyroid disease, the more severe the mood changes. It can cause anxiety, nervousness, irritability, depression, unusual tiredness, loss of apetite, lack of concentration, short temper and anger. - Sex hormones have both organizational and activational effects in the central nervous system. Energy levels are heavily dependent on our hormones. And with so many hormones involved, it can be difficult to isolate exactly which ones are responsible for changes in the energy level. Here are a few to consider when detangling your decreased energy health; - Thyroid hormones ; they are responsible for maintaining balance in the body, affecting temperature, metabolism, heart rate, mood, and energy levels. When you experience hypothyroidism, which is abnormally low thyroid hormones, many body systems slow down, leading to fatigue and low energy. Less energy consumed can lead to weight gain, slower digestion leads to constipation, and the decreasing serotonin levels may result in depression. - Adrenal hormones ; cortisol responds to the body's energy needs by regulating metabolism and hunger. Chronic stress can disrupt this system and damage your body's ability to function optimally. - Estrogen and progesterone ; when these levels fluctate or drop sharply, many women experience uncomfortable symptoms like hot flashes, mood swings, vaginal dryness, and bone thinning/increased fracture risk. Both low and high estrogen levels may also effect your energy levels significantly. For women, hormone levels can shift dramatically during perimenopause and menopause, whereas men typically experience a slow and gradual decline beginning around age 30. So both men and women can develop symptoms and see their energy levels decline as they approach middle age. Unfortunately, imbalances in a variety of hormones often have similar symptoms. Additionally, an imbalance of one hormone may cascade into more complex conditions since many hormones directly impact each other. Digestion hormones regulate the system that produces them, functioning largely independent from the rest of the endocrine system. When food enters the stomach, the wall where the stomach joins the small intestine, gastrin is released, which promotes the flow of acid from the gastric glands in the stomach. These glands also release pepsinogen which is the inactive form of the protein digesting enzyme pepsin, but this process is primarily under nervous control. The entry of the acidified stomach contents into the first part of the small intestine releases secretin (a digestive hormone) and cholecystokinin. Secretin promotes the discharge of fluid and bicarbonate ions from the pancreas and promotes the secretion of bile from the liver, which aids in the digestion of fats. Blood sugar is influenced by several hormones. These are: - Insulin ; Enhances entry of glucose into cells and storage of glucose as glycogen, or conversion to fatty acids. It also enhances synthesis of fatty acids and proteins and suppresses breakdown of protein into amino acids and triglycerids into free fatty acids. - Amylin ; Suppresses glucagon secretion after eating and slows gastric emptying. It also reduces food intake. - GIP ; Induces insulin secretion, inhibits apoptosis of the pancreatic beta cells and promotes their proliferation. It also stimulates glucagon secretion and fat accumulation. - Glucagon ; Enhances release of glucose from glycogen and synthesis of glucose from amino acids or fats. - Asprosin ; Enhances release of liver glucose during fasting. - Somatostatin ; Suppresses release of insulin, pituitary tropic hormones, gastrin and secretin. It also decreases stomach acid production by preventing the release of other hormones (gastrin and histamine), thus slowing down the digestive process. - Epinephrine ; Enhances release of glucose from glycogen and fatty acids from adipose tissue. - Cortisol ; Enhances gluconeogenesis and antagonizes insulin. - ACTH ; Enhances release of cortisol and fatty acids from adipose tissue. - Growth hormone ; Antagonizes insulin. - Thyroxine ; Enhances release of glucose from glycogen and absorption of sugars from intestine. Sexual drive : Libido naturally varies from person to person. It can also change throughout life. However, the sex hormones testosterone and estrogen, together with the neurotransmitters dopamine and oxytocin regulates libido. Blood pressure is regulated by the hormone aldosterone (ALD) by managing the levels of salt (sodium) and potassium in your blood and impacting blood volume. Your blood pressure can also be impacted by several other hormones: - Adrenal glands ; if the adrenal glands make too much aldosterone, cortisol or adrenaline-like hormones, it can cause high blood pressure. - Thyroid gland ; high blood pressure can be caused by an underactive or overactive thyroid gland. - Pituitary gland ; sometimes problems with the adrenal glands and thyroid gland are due to problems with the pituitary gland. If the pituitary gland sends too much signal to the adrenal galnds or thyroid gland, it can result in high blood pressure. - Parathyroid glands ; if the parathyroid glands make too much parathyroid hormone, it can cause high blood pressure. - Pancreas ; high blood pressure in adults with obesity may be partially due to elevated insulin levels and insulin resistance. The nervous system is designed to protect us from danger through its interpretation of, and reactions to, stimuli. But a primary function of the sympathetic and parasympathetic nervous systems is to interact with the endocrine system to elicit chemicals that provide another system for influencing our feelings and behaviours. When the hormones released by one gland arrive at receptor tissues or other glands, these recieving receptors may trigger the release of other hormones, resulting in a series of complex chemical chain reactions. The endocrine system works together with the nervous system to influence many aspects of human behaviour, including growth, reproduction and metabolism. And the endocrine system also plays a vital role in emotions.

https://www.britannica.com/biography/George-Redmayne-Murray George Redmayne Murray, (born June 20, 1865, Newcastle-upon-Tyne, Northumberland, Eng.—died Sept. 21, 1939, Mobberley, Cheshire), English physician who pioneered in the treatment of endocrine disorders. He was one of the first to use extractions of animal thyroid to relieve myxedema (severe hypothyroidism) in humans. George, the son of a prominent physician, William Murray, received clinical training at University College Hospital, London. He was awarded both his M.B. (1889) and M.D. (1896) by the University of Cambridge. Determined to pursue a career in experimental medicine, Murray in 1891 became pathologist to the Hospital for Sick Children in Newcastle. He also lectured in bacteriology and comparative anatomy at Durham University. From 1893 to 1908 he was Heath professor of comparative pathology at Durham. Appointed to the chair of medicine at Manchester University, he remained there to the end of his career. In 1891 Murray published his most important research, a report in the British Medical Journal on the effectiveness of sheep thyroid extract in treating myxedema in humans. Thyroid deficiency had been recognized as the cause of myxedema in the 1880s, and several researchers had established that an animal could survive the usually fatal effects of thyroidectomy if part of the excised thyroid gland was transplanted to another body location. Sir Victor Horsley, a colleague of Murray’s, later suggested that part of a sheep’s thyroid could be transplanted into human patients to relieve myxedema. Murray surmised, however, that a hypodermic injection of thyroid extract could more effectively be used to correct myxedema in humans, and he was completely successful in his first such attempt at treatment. Subsequent tests substantiated his approach. George Murray was born at Newcastle, the son of William Murray, F.R.C.P. He was educated at Eton and Trinity College, Cambridge, being placed in the first class of the natural sciences tripos of 1886. He qualified in medicine at University College London, in 1888, receiving the Fellowes gold medal in the same year, and completed his training with visits to Berlin and Paris. He acted as house physician in University College Hospital before starting practice in his native city, where he was appointed in 1891 pathologist to the Hospital for Sick Children and lecturer on bacteriology at Durham University. In 1891, too, he made his reputation by being the first to treat myxoedema with thyroid extract given by injection. In 1893 he was made Heath professor of comparative pathology in the University and in 1898 physician to the Royal Victoria Hospital, Newcastle. He relinquished both appointments in 1908 when he was chosen to fill the chair of medicine at Manchester University, which carried with it the office of physician to the Manchester Royal Infirmary. In the 1914—1918 War he served with the 2nd Western General and 57th General Hospitals, and from 1918 to 1919 as consulting physician, with the rank of colonel, to the British forces in Italy. He was a member of the Medical Research Council from 1916 to 1918. He was a contributor to Quain’s Dictionary and Allbutt’s System of Medicine, and at the Royal College of Physicians delivered the Goulstonian Lectures in 1899 and the Bradshaw Lecture in 1905. He resigned his offices at Manchester in 1925, and in retirement lived at Mobberley in Cheshire. Murray was a man of high ability and unassuming friendliness — qualities which effectively dispelled the opposition to his appointment at Manchester in 1908. He married in 1892 Annie, daughter of Edward Robert Bickersteth of Liverpool, and had three sons and one daughter. He died at Mobberley. G H Brown

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).

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 Hopkins Medicine https://www.hopkinsmedicine.org/health/conditions-and-diseases/hashimotos-thyroiditis Original language: English Thyroiditis is when your thyroid gland becomes irritated. Hashimoto's thyroiditis is the most common type of this health problem. It is an autoimmune disease. It occurs when your body makes antibodies that attack the cells in your thyroid. The thyroid then can't make enough of the thyroid hormone. Many people with this problem have an underactive thyroid gland. That's also known as hypothyroidism. They have to take medicine to keep their thyroid hormone levels normal. What is the cause of Hashimoto’s thyroiditis? Hashimoto's thyroiditis is an autoimmune disorder. Normally, your autoimmune system protects your body by attacking bacteria and viruses. But with this disease, your immune system attacks your thyroid gland by mistake. Your thyroid then can't make enough thyroid hormone, so your body can't work as well. Who is at risk for Hashimoto’s thyroiditis? Things that may make it more likely to you for to get Hashimoto’s thyroiditis are: Being a woman. Women are about 7 times more likely to have the disease. Hashimoto's thyroiditis sometimes begins during pregnancy. Middle age. Most cases happen between 40 to 60 years of age. But it has been seen in younger people. Heredity. The disease tends to run in families. But no gene has been found that carries it. Autoimmune diseases. These health problems raise a person’s risk. Some examples are rheumatoid arthritis and type 1 diabetes. Having this type of thyroiditis puts you at higher risk for other autoimmune illnesses. What are the symptoms of Hashimoto's thyroiditis? Each person's symptoms may vary. Symptoms may include: Goiter This is an enlargement of your thyroid gland. It causes a bulge on your neck. It is not cancer. But it can cause problems like pain or trouble with swallowing, breathing, or speaking. Underactive thyroid When your thyroid doesn’t make enough thyroid hormone, it can cause these symptoms: Tiredness Muscle weakness Weight gain Being cold bothers you Depression Hair and skin changes Overactive thyroid When the thyroid is attacked by antibodies, it may at first make more thyroid hormone. This is called Hashitoxicosis. It does not happen to everyone. But it can cause these symptoms: Being hot bothers you Rapid heart rate Sweating Weight loss Tremors Anxiety These symptoms may look like other health problems. Always see your healthcare provider for a diagnosis. How is Hashimoto thyroiditis diagnosed? Your healthcare provider will ask about your medical history and give you a physical exam. You will also have blood tests. These can measure your thyroid hormone levels and check for some antibodies to proteins in the thyroid. How is Hashimoto's thyroiditis treated? Your healthcare provider will figure out the best treatment for you based on: Your age, overall health, and medical history How sick you are How well you handle certain medicines, treatments, or therapies If your condition is expected to get worse Your opinion or preference You will not need treatment if your thyroid hormone levels are normal. But Hashimoto's thyroiditis often looks like an underactive thyroid gland. If so, it can be treated with medicine. The medicine replaces lost thyroid hormone. That should stop your symptoms. It can also ease a goiter if you have one. A goiter can cause problems like pain or trouble swallowing, breathing, or speaking. If these symptoms don't get better, you may need surgery to remove the goiter. When should I call my healthcare provider? Tell your healthcare provider if your symptoms get worse or you have new symptoms. Key points about Hashimoto’s thyroiditis Hashimoto's thyroiditis can cause your thyroid to not make enough thyroid hormone. It is an autoimmune disease. It occurs when your body makes antibodies that attack the cells in your thyroid. Symptoms may include an enlarged thyroid gland (goiter), tiredness, weight gain, and muscle weakness. You don’t need treatment if your thyroid hormone levels are normal. If you have an underactive thyroid, medicine can help. Next steps Tips to help you get the most from a visit to your healthcare provider: Know the reason for your visit and what you want to happen. Before your visit, write down questions you want answered. Bring someone with you to help you ask questions and remember what your provider tells you. At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you. Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are. Ask if your condition can be treated in other ways. Know why a test or procedure is recommended and what the results could mean. Know what to expect if you do not take the medicine or have the test or procedure. If you have a follow-up appointment, write down the date, time, and purpose for that visit. Know how you can contact your provider if you have questions.

Written by Bjørn O Asvold, Trine Bjøro, Tom Ivar L Nilsen, David Gunnell, Lars J Vatten 2008 Apr 28;168(8):855-60. doi: 10.1001/archinte.168.8.855. Abstract Background: Recent studies suggest that relatively low thyroid function within the clinical reference range is positively associated with risk factors for coronary heart disease (CHD), but the association with CHD mortality is not resolved. Methods: In a Norwegian population-based cohort study, we prospectively studied the association between thyrotropin levels and fatal CHD in 17,311 women and 8002 men without known thyroid or cardiovascular disease or diabetes mellitus at baseline. Results: During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of these, 192 women and 164 men had thyrotropin levels within the clinical reference range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range were positively associated with CHD mortality (P for trend = .01); the trend was statistically significant in women (P for trend = .005) but not in men. Compared with women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. Conclusions: Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD. See the full study here: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/414170

https://www.functionalps.com/blog/2011/12/05/achilles-tendon-reflex/ Written by Team FPS, December 5, 2011 Quotes by Ray Peat, PhD: “One of the oldest tests for hypothyroidism was the Achilles tendon reflex test in which the rate of relaxation of the calf muscle corresponds to thyroid function–the relaxation is slow in hypothyroid people. Water, sodium, and calcium are more slowly expelled by the hypothyroid muscle. Exactly the same slow relaxation occurs in the hypothyroid heart muscle, contributing to heart failure, because the semi-contracted heart can’t receive as much blood as the normally relaxed heart. The hypothyroid blood vessels are unable to relax properly, contributing to hypertension. Hypothyroid nerves don’t easily return to their energized relaxed state, leading to insomnia, parasthesias, movement disorders, and nerves that are swollen and very susceptible to pressure damage.” “The thyroid hormone keeps the cellular energy high, the adrenaline low, and reflexes strong. It undoubtedly has an important effect on both perception and responses. In the high energy, expansive state, with tresholds raised, strong stimulus could evoke a strong response. Things are bigger, possibilities are greater.” “Checking the relaxation rate of the Achilles reflex is a quick way to check the effect of the thyroid on your nerves and muscles; the relaxation should be instantaneous, loose and floppy.” “There are several convenient indicators of the metabolic rate–the daily temperature cycle and pulse rate (the temperature should rise after breakfast), the amount of water lost by evaporation, and the speed of relaxation of muscles (Achilles reflex relaxation).” “Measuring the speed and relaxation of the Achilles tendon reflex twitch is a traditional method for judging thyroid function, because in hypothyroidism the relaxation is visibly delayed.” Delayed relaxation of the muscle stretch reflex (Woltman’s Sign) occurs in hypothyroidism. The achilles tendon reflex is a scientific way to assess thyroid function. The foot should plantar flex quickly and then return immediately to its starting position or beyond with no hesitation if the metabolism is healthy. No response or a very slow return back to original position are indicative of low metabolism. J Clin Neurosci. 2013 Mar 18. pii: S0967-5868(13)00040-4. doi: 10.1016/j.jocn.2012.09.047. The origin of Woltman’s sign of myxoedema Burkholder DB, Klaas JP, Kumar N, Boes CJ. Woltman’s sign of myxoedema, named after Henry Woltman in 1956, is the delayed relaxation phase of the muscle stretch reflex in patients with myxoedema. Although a change in these reflexes was mentioned as being clinically evident possibly as early as the 1870s, no formal description was published until 1924 when William Calvert Chaney objectively quantified the change. Woltman was involved in training Chaney, and it has been proposed that he guided Chaney’s study of these reflexes. Despite the attachment of Woltman’s name to the eponym, little evidence exists that directly links him to the first objective study of the muscle stretch reflex in myxoedema performed by Chaney. Woltman’s Sign of Hypothyroidism Mark A. Marinella Minerva Med. 1976 Oct 27;67(51):3325-34. Achilles reflexogram and hemodynamic parameters in the evaluation of thyroid function [Article in Italian] Franco G, Malamani T. Among the numerous techniques designed to explore thyroid function, two which examine important peripheral aspects are considered: Achilles osteotendinous reflectivity (determination of contraction time and relaxation time of the gastrocnemius muscle) and the response of the cardiovascular system to thyroid hormones (determination of the time of onset of Korotkoff’s sound and that of the brachial sphygmic wave). Comparison of the results obtained with these two techniques in a group of 60 euthyroid subjects, 17 hypothyroid and 25 hyperthyroid cases, shows that the techniques are comparable as regards precision, reproducibility, and sensitivity and are of indubitable importance for the assessment of thyroid function through the study of two of its peripheral aspects. Probl Endokrinol (Mosk). 1982 Jan-Feb;28(1):34-8. Reflexometry as a supplementary study method in thyroid hypofunction [Article in Russian] Gaĭdina GA, Matveeva LS, Lazareva SP. A correlation was established between the time of the Achilles reflex and the biochemical characteristics of thyroid function (total thyroxin and triiodothyronine levels, thyroxin-binding capacity of the blood serum proteins, the basal TTH level) in patients with grave and moderately expressed hypothyroidism. This correlation was retained during the substitution therapy: however, the reflex time recovery was retarded as compared to the degree of manifestation of the clinical symptoms and normalization of the biochemical parameters. The time of the Achilles jerk may serve as an additional criterion in evaluating the hypothyrosis severity and the effect of the treatment. J Assoc Physicians India. 1990 Mar;38(3):201-3. Ankle reflex photomotogram in thyroid dysfunctions Khurana AK, Sinha RS, Ghorai BK, Bihari N. The tap to half relaxation time of tendon achilles reflex was measured in thirty control subjects, forty-five thyrotoxic and sixty hypothyroid patients. The half relaxation time in the control males and females was 279.33 +/- 76.39 msec and 320.00 +/- 52.37 msec. respectively. In thyrotoxic males and females the half relaxation time was 256.67 +/- 31.62 msec (P less than 0.01) and 252.50 +/- 47.68 msec (P less than 0.01) respectively. Amongst the hypothyroid male and female patients the half relaxation time was 405.0 +/- 35.56 msec (P less than 0.01) and 422.5 +/- 115.36 (P less than 0.01) respectively. As all these values were statistically significant, we consider the photomotographic measurement of ankle reflex as an important aid to the diagnosis of thyroid hormone imbalances. Aust Fam Physician. 1976 May;5(4):550-9, 561. A screening test for thyroid function Goodman E. The Achilles tendon reflex half relaxation time measurement (ART) has been used by many physicians both as a diagnostic test and for the assessment of progress in thyroid gland malfunction. Reference is made to some results obtained in Melbourne and in other countries using different methods of measurement of the ART for these purposes. In a series of 2064 patients referred to the Shepherd Foundation Centre, the Achilles tendon reflex half relaxation time was measured by means of the SMI Reflexometer and a comparison was made in each case with a laboratory estimation of the T3 resin uptake and T4 total thyroxine iodine and the Free Thyroxine Index (FTI). Reference is made to a survey conducted among referring doctors where opinions were sought as to the clinical usefulness of different tests including the Achilles tendon reflex time measurement. Probl Endokrinol (Mosk). 1987 May-Jun;33(3):6-9. Changes in the duration of the Achilles reflex in euthyroid goiter in children [Article in Russian] Gaĭdina GA, Alekseeva RM, Bobrovskaia TA, Lazareva SP. Changes in the duration of the Achilles reflex were studied in subclinical disturbances of thyroid function. For this purpose the duration of the Achilles reflex, the levels of T4, T3, iodine protein bound TSH and cholesterol were investigated in children admitted to hospital with the general diagnosis of the “euthyroid goiter”. Clinical and laboratory findings revealed subclinical types of the diffuse toxic goiter, hypothyrosis, chronic thyroiditis, endemic goiter, nodular goiter, pubertal struma and sporadic euthyroid goiter. The aim of the study was to define the diagnostic importance of reflexometry in subclinical disorders of thyroid function and to assess the relationships between metabolic derangements and the duration of the Achilles reflex. Changes in the duration were shown to correspond to disorder of thyroid function. In 76% of the cases reflexometry brought about the correct assessment of the patient’s thyroid status. A significant conformity of the levels of TSH, T3, T4 to the duration of the Achilles reflex was shown. Med Klin. 1970 Nov 6;65(45):1973-82. Validity of Achilles tendon reflex measurement during thyroid gland function disorders [Article in German] Gillich KH, Krüskemper HL, Stendel A. “A study published in the Journal of Clinical Endocrinology and Metabolism assessed the level of hypothyroidism in 332 female patients based on a clinical score of 14 common signs and symptoms of hypothyroidism and assessments of peripheral thyroid action (tissue thyroid effect). The study found that the clinical score and ankle reflex time correlated well with tissue thyroid effect but the TSH had no correlation with the tissue effect of thyroid hormones (118). The ankle reflex itself had a specificity of 93% (93% of those with slow relaxation phase of the reflexes had tissue hypothyroidism) and a sensitivity of 77% (77% of those with tissue hypothyroidism had a slow relaxation phase of the reflexes) making both the measurement of the reflex speed and clinical assessment a more accurate measurement of tissue thyroid effect than the TSH.” -from How Accurate is TSH Testing? J Clin Endocrinol Metab. 1997 Mar;82(3):771-6. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ. The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol. Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 +/- 2.7 vs. 4.4 +/- 2.2 vs. 3.4 +/- 2.0; P < 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 +/- 1.6 vs. 2.1 +/- 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P < 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P < 0.0004), and that with T3 was r = -0.56 (P < 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005). Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment. CMAJ August 12, 2008 vol. 179 no. 4 387 Woltman’s Sign in the bicep tendon Sanju Cyriac MD, Sydney C. d’Souza MD, Dhiraj Lunawat MBBS, Pai Shivananda MD, Mukundan Swaminathan MBBS Video showing the Woltman sign in the bicep tendon of a 55-year-old woman A 55-year-old woman presented to hospital with a 2-month history of facial puffiness, constipation, hoarse voice, fatigue and cold intolerance. She had no history of illness, and she was not taking any medication. On examination, her vital signs were normal, and she was not in distress. Her voice was hoarse, and she had facial and pedal edema, yellow skin and delayed relaxation of deep tendon reflexes in her upper and lower limbs (Figure 1, Video 1, available online at www.cmaj.ca/cgi/content/full/179/4/387/DC1). The results of laboratory investigations revealed severe hypothyroidism, which was successfully managed with thyroid hormone replacement therapy. Severe hypothyroidism is rarely seen in clinical practice in the developed world because of the widespread availability of thyroid-stimulating hormone and assays to detect thyroid hormone. Symptoms of hypothyroidism include fatigue, cold intolerance, dyspnea, weight gain, constipation, hair loss, dry skin and menstrual irregularities. Typical findings on physical examination include dry coarse skin, periorbital and pedal edema, bradycardia, thin hair and pleural effusions. Delayed relaxation of deep tendon reflexes (Woltman sign)1 is seen in about 75% of patients with hypothyroidism and has a positive predictive value of 92% in overtly hypothyroid patients.2 In unaffected patients, the relaxation time for deep tendon reflexes is 240–320 ms. Delays in relaxation time in patients with hypothyroidism appears to be proportional to the level of thyroid-hormone deficiency. As sensitive blood assays become more widely available around the world, the Woltman sign is likely to become obsolete as a diagnostic tool.

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: 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". 1891: Murray treats patients with Thyroid extract injections. Soon after, oral agents are used and tablets are made. 1915: Kendall makes a crystalline powder from Thyroid. It is assumed that Thyroxin is the active substance in Thyroid. 1950-tallet: T3, liothyronine was isolated and made chemically. It was not realized that there was more to Thyroid USP than T4 until then. 1950: Thyroxin-Natrium registered in Norway. 1952: T3 was discovered, important information because Thyroxin-Natrium was introduced as identical to Thyroid extract before anyone knew anything about the active ingredient T3, and that it was missing in Thyroxin-Natrium. But from before it was known that T2 was 80% of the amount of Thyroxine types in Thyroid extract, but it did not work in trials so this was written off as not important. 1958: Synthroid enters the US market. 1962: Medicines that were recognized as effective before that did not need to apply for new approval later. This is a principle known as "Grandfathered In". 1997: The FDA decides that all Thyroxin preparations are new drugs and must submit an application for approval of a new drug. Not long after, Thyrolar, a T4/t3 combination preparation (Liotrix) is approved as the first preparation. 2000: Unithyroid is approved as the first levothyroxine preparation in the USA. Note that Thyrolar (a T4/T3 combo owned by Forest) sought and received approval long before any Levothyroxine preparations. Armor Thyroid and all Thyroid USP were always approved. 2001: Abbott which now owns Synthroid submits an NDA application. July 2002: Synthroid approved. 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: IV. Formulation Change Because orally administered levothyroxine sodium products are marketed without approved applications, manufacturers have not sought FDA approval each time they reformulate their products. In 1982, for example, one manufacturer reformulated its levothyroxine sodium product by removing two inactive ingredients and changing the physical form of coloring agents (Ref. 6). The reformulated product increased significantly in potency. One study found that the reformulated product contained 100 percent of stated content compared to 78 percent before the reformulation (Ref. 7). Another study estimated that the levothyroxine content of the old formulation was approximately 70 percent of the stated value (Ref. 8). This increase in product potency resulted in serious clinical problems. On January 17, 1984, a physician reported to FDA: ''I have noticed a recent significant problem with the use of [this levothyroxine sodium product]. People who have been on it for years are suddenly becoming toxic on the same dose. Also, people starting on the medication become toxic on 0.1 mg [milligram] which is unheard of.'' On May 25, 1984, another physician reported that 15 to 20 percent of his patients using the product had become hyperthyroid although they had been completely controlled up until that time. Another doctor reported in May 1984 that three patients, previously well-controlled on the product, had developed thyroid toxicity. One of these patients experienced atrial fibrillation. There is evidence that manufacturers continue to make formulation changes to orally administered levothyroxine sodium products. As discussed in section V of this document, one manufacturer is reformulating in order to make its product stable at room temperature. In a 1990 study (Ref. 5), one manufacturer's levothyroxine sodium tablets selected from different batches showed variations in chromatographs suggesting that different excipients had been used. V. Stability Problems FDA, in conjunction with the United States Pharmacopeial Convention, took the initiative in organizing a workshop in 1982 to set the standard for the use of a stability-indicating high-performance liquid chromatographic (HPLC) assay for the quality control of thyroid hormone drug products (Ref. 3). The former assay method was based on iodine content and was not stability-indicating. Using the HPLC method, there have been numerous reports indicating problems with the stability of orally administered levothyroxine sodium products in the past several years. Almost every manufacturer of orally administered levothyroxine sodium products, including the market leader, has reported recalls that were the result of potency or stability problems. Since 1991, there have been no less than 10 firm-initiated recalls of levothyroxine sodium tablets involving 150 lots and more than 100 million tablets. In all but one case, the recalls were initiated because tablets were found to be subpotent or potency could not be assured through the expiration date. The remaining recall was initiated for a product that was found to be superpotent. During this period, FDA also issued two warning letters to manufacturers citing stability problems with orally administered levothyroxine sodium products. At one firm, potency problems with levothyroxine sodium tablets resulted in destruction of products and repeated recalls. From 1990 to 1992, the firm destroyed 46 lots of levothyroxine sodium tablets that failed to meet potency or content uniformity specifications during finished product testing. In August 1989, this firm recalled 21 lots due to subpotency. In 1991, the firm recalled 26 lots in February and 15 lots in June because of subpotency. An FDA inspection report concerning another manufacturer of levothyroxine sodium showed that 14 percent of all lots manufactured from 1991 through 1993 were rejected and destroyed for failure to meet the assay specifications of 103 to 110 percent established by the firm. In March 1993, FDA sent a warning letter to a firm stating that its levothyroxine tablets were adulterated because the expiration date was not supported by adequate stability studies. Five lots of the firm's levothyroxine sodium tablets, labeled for storage within controlled room temperature range, had recently failed stability testing when stored at the higher end of the range. The warning letter also objected to the labeled storage conditions specifying a nonstandard storage range of 15 to 22 degrees C. FDA objected to this labeling because it did not conform to any storage conditions defined in United States Pharmacopeia (USP) XXII. In response, the firm changed the labeling instruction to store the product at 8 to 15 degrees C. The firm informed FDA that it would reformulate its levothyroxine sodium tablets to be stable at room temperature. The five failing lots named in FDA's warning letter were recalled in April 1994. Previously, in December 1993, a lot of levothyroxine sodium tablets was recalled by the same firm because potency was not assured through the expiration date. In November 1994, the renamed successor firm recalled one lot of levothyroxine sodium tablets due to superpotency. Another firm recalled six lots of levothyroxine sodium tablets in 1993 because they fell below potency, or would have fallen below potency, before the expiration date. The USP specifies a potency range for levothyroxine sodium from 90 percent to 110 percent. Analysis of the recalled tablets showed potencies ranging from 74.7 percent to 90.4 percent. Six months later, this firm recalled another lot of levothyroxine sodium tablets when it fell below labeled potency during routine stability testing. Content analysis found the potency of the failed lot to be 85.5 percent to 86.2 percent. Subsequently, an FDA inspection at the firm led to the issuance of a warning letter regarding the firm's levothyroxine sodium products. One of the deviations from good manufacturing practice regulations cited in that letter was failure to determine by appropriate stability testing the expiration date of some strengths of levothyroxine sodium. Another deviation concerned failure to establish adequate procedures for monitoring and control of temperature and humidity during the manufacturing process. In April 1994, one manufacturer recalled seven lots of levothyroxine sodium products because potency could not be assured through the expiration date. In February 1995, the same manufacturer initiated a major recall of levothyroxine sodium affecting 60 lots and 50,436,000 tablets. The recall was initiated when the product was found to be below potency at 18-month stability testing. In December 1995, a manufacturer recalled 22 lots of levothyroxine sodium products because potency could not be assured through the expiration date. In addition to raising concerns about the consistent potency of orally administered levothyroxine sodium products, this pattern of stability problems suggests that the customary 2-year shelf life may not be appropriate for these products because they are prone to experience accelerated degradation in response to a variety of factors. Levothyroxine sodium is unstable in the presence of light, temperature, air, and humidity (Ref. 4). One study found that some excipients used with levothyroxine sodium act as catalysts to hasten its degradation (Ref. 5). In addition, the kinetics of levothyroxine sodium degradation is complex. Stability studies show that levothyroxine sodium exhibits a biphasic first order degradation profile, with an initial fast degradation rate followed by a slower rate (Ref. 4). The initial fast rate varies depending on temperature. To compensate for the initial accelerated degradation, some manufacturers use an overage of active ingredient in their formulation, which can lead to occasional instances of superpotency." I got comments on the above on the thyroid.about.com forum when I posted this text that Mary Shomon has on her website. They asked if I was aware of what the Federal Registry was. It is where all laws and everything that is important and official is recorded in the United States, the most official that exists in America. "The document you quote is the Federal Register notice that declared all T4s marketed in the US to be unapproved drugs and in need of NDAs. It's a very significant document and should be required reading for all thyroid patients, in my honest opinion. (Since you're not in the US, you may not know that the Federal Register is the publication organ of the US government. If something's an official decision by any federal agency, it's published in the Federal Register.)" http://forums.about.com/n/pfx/forum.aspx?msg=73147.54&nav=messages&webtag=ab-thyroid#a54 During the same period, no problems with Thyroid were reported. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12729477&dopt=Abstract Levothyroxine a new drug? Since when? How could that be? (paylink) 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 inequivalent unless equivalence has been established and noted in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)." How is levothyroxine tested? Not on sick people. One gives healthy people high doses and measures how high the blood tests go: http://www.medscape.com/viewarticle/472917 "For pharmacokinetic studies designed to measure the bioavailability of LT4 formulations, the Food and Drug Administration (FDA)[8] recommends that a single dose be administered to healthy subjects at a strength several times the normal therapeutic dose. The objective is to raise serum concentrations of the hormone sufficiently above endogenous baseline levels to achieve meaningful pharmacokinetic measurements."... "The most recent clinical practice guidelines from the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association recognize that the various brands of LT4 have not been proven bioequivalent and recommend that the patient's brand not be changed during therapy.." In this study, they used data from 31 healthy people who received a larger dose of thyroxine twice 44 days apart. 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. From Gabys article, http://www.ncbi.nlm.nih.gov/pubmed/15253676 Here from page 15 in this link at findarticles.com: Objections to the Use of Armour Thyroid The main objections voiced in textbooks and editorials 1,73 regarding the use of desiccated thyroid are: (1) its potency varies from batch to batch, and (2) the use of T3-containing preparations causes the serum T3 concentration to rise to supraphysiological levels. Regarding between-batch variability, there may have been some problems with quality control a half-century or more ago, and in a 1980 study a number of generic versions of desiccated thyroid were still found to be unreliable in their potency. The amounts of T4 and T3 in Armour thyroid, on the other hand, were found to be constant.74 Moreover, two-year old tablets of Armour thyroid contained similar amounts of T4 and T3 as did fresh tablets. Three studies are typically cited to support the contention that T3 containing preparations should not be used. Smith et al reported a levothyroxine-plus-T3 product caused adverse side effects in 46 percent of patients; whereas, side effects occurred in only 10 percent of those receiving levothyroxine alone.75 In that study, however, the combination product and the levothyroxine product differed substantially in potency. For the combination treatment, each 100 mcg of levothyroxine was replaced by 80 mcg of levothyroxine plus 20 mcg of T3. Considering 20mcg of T3 is equivalent to 80 mcg of levothyroxine, the total hormone dose in the combination product was 60-percent greater than that in the levothyroxine preparation. Therefore, the high incidence of adverse side effects may not have been due to the T3, but to the higher total dose of thyroid hormones. In the second study, by Surks et al, the administration of T3-containing preparations to hypothyroid patients caused the plasma T3 concentration to become markedly elevated for several hours after ingestion of the medication.76 In most cases, however, the amount of T3 administered (50-75 mcg) was considerably greater than that contained in a typical dose of desiccated thyroid (9 mcg T3 per 60 mg),77 and/or the total dose of thyroid hormones given was excessive (180 mcg of levothyroxine plus 45 mcg of T3). By contrast, in a patient given 60 mg of desiccated thyroid, the plasma T3 concentration increased from a hypothyroid level to a euthyroid level. Of two hypothyroid patients treated with 120 mg per day of desiccated thyroid, one showed a relatively constant plasma concentration of T3. In the other patient, the T3 level increased by a maximum of 80 percent, to the bottom of the range seen in hyperthyroid patients, and returned to the baseline value within 24 hours. In that patient, the pre-dose plasma T3 concentration was near the top of the normal range, suggesting that this patient may have been receiving too high a dose of desiccated thyroid. Finally, Jackson and Cobb reported that the serum T3 concentration (measured 2-5 hours after a dose) was above normal in most patients receiving desiccated thyroid.2 They concluded there is little use for desiccated thyroid in clinical medicine. Most of the patients (87.5%) in that study, however, were taking a relatively large dose of desiccated thyroid (120-180 mg daily). Moreover, 57.5 percent of the patients were not being treated for hypothyroidism, but rather to suppress the thyroid gland. Nearly half of the patients continued to have an elevated serum T3 concentration after they were switched to levothyroxine, even though the equivalent dose was reduced in 62.5 percent of patients. Thus, the elevated serum T3 concentrations found in this study can be explained in large part by the high doses used and by the selection of patients, the majority of whom were not hypothyroid. What this study does suggest is that desiccated thyroid should not be used for thyroid-suppression therapy. Although the oral administration of T3 causes a transient increase in serum T3 concentrations, that fact does not appear to be of significance for hypothyroid patients receiving usual replacement doses of Armour thyroid. In this author's experience, reports of post-dose symptoms of hyperthyroidism are extremely rare, even among patients taking larger doses of desiccated thyroid. An occasional patient reports feeling better when he or she takes Armour thyroid in two divided doses daily. The nature of that improvement, however, is usually an increase in effectiveness, rather than a reduction in side effects. For patients taking relatively large amounts of desiccated thyroid (such as 120 mg daily or more), splitting the daily dose would obviate any potential concern about transient elevations of T3 levels. In practice, however, splitting the daily dose is rarely necessary. http://www.unboundmedicine.com/medline/ebm/research/Armour_thyroid A search engine for articles: http://www.unboundmedicine.com/medline/ebm/mesh/Thyroid_Gland,_Desiccated