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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.

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."

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.

BMC Endocr Disord. 2019; 19: 37. Published online 2019 Apr 18. doi:  10.1186/s12902-019-0365-4 Written by John E. M. Midgley,  Anthony D. Toft ,  Rolf Larisch ,  Johannes W. Dietrich  and Rudolf Hoermann Background In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and statistical viewpoints. An increasing frequency of hypothyroid-like complaints is noted in patients in the wake of this directional shift, together with relaxation of treatment targets. Recent prospective and retrospective studies suggested a changing pattern in patient complaints associated with recent guideline-led low-dose policies. A resulting dramatic rise has ensued in patients, expressing in various ways dissatisfaction with the standard treatment. Contributing factors may include raised problem awareness, overlap of thyroid-related complaints with numerous non-specific symptoms, and apparent deficiencies in the diagnostic process itself. Assuming that maintaining TSH anywhere within its broad reference limits may achieve a satisfactory outcome is challenged. The interrelationship between TSH, free thyroxine (FT4) and free triiodothyronine (FT3) is patient specific and highly individual. Population-based statistical analysis is therefore subject to amalgamation problems (Simpson’s paradox, collider stratification bias). This invalidates group-averaged and range-bound approaches, rather demanding a subject-related statistical approach. Randomised clinical trial (RCT) outcomes may be equally distorted by intra-class clustering. Analytical distinction between an averaged versus typical outcome becomes clinically relevant, because doctors and patients are more interested in the latter. It follows that population-based diagnostic cut-offs for TSH may not be an appropriate treatment target. Studies relating TSH and thyroid hormone concentrations to adverse effects such as osteoporosis and atrial fibrillation invite similar caveats, as measuring TSH within the euthyroid range cannot substitute for FT4 and FT3 concentrations in the risk assessment. Direct markers of thyroid tissue effects and thyroid-specific quality of life instruments are required, but need methodological improvement. Conclusion It appears that we are witnessing a consequential historic shift in the treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH. The focus on biochemistry rather than patient symptom relief should be re-assessed. A joint consideration together with a more personalized approach may be required to address the recent surge in patient complaint rates. Background The clinical state of hypothyroidism (then known as myxoedema) was described around 1870, and 10 years later it was recognised as being due to loss of function of the thyroid gland [ 1 – 4 ]. While the Chinese may have been treating goitre in cretins with sheep’s thyroid in the sixth century BCE [ 5 ], initial attempts at treating hypothyroidism were made by transplantation of animal thyroid tissue, followed by injectable and oral formulations [ 5 – 7 ]. In 1914, Kendall [ 8 ] was the first to purify the hormone thyroxine at Mayo Laboratories, which was synthesised as levothyroxine (LT4) in 1926 [ 9 ]. Despite this early chemical breakthrough in drug manufacturing, desiccated animal thyroid extract remained widely used, and even at this time some patients still regard it as the most satisfactory treatment of hypothyroidism for them [ 10 , 11 ]. A policy was adopted by endocrinologists in the 1960s to replace thyroid extract with synthetic levothyroxine as the latter was then more consistent in its content [ 12 – 15 ]. More recently, thyroid extracts have been standardized by modern high pressure liquid chromatography (HPLC) techniques to maintain their content of thyroid hormones in different batches within USP specifications. Few clinical trials have been performed to compare the efficacy of the two products [ 15 ], and an exploratory RCT was conducted only in 2013 [ 16 ]. From its very beginnings replacement therapy was individualised and guided by the measurement of basal metabolic rate, a peripheral marker of the adequacy of thyroid hormone action [ 17 ]. Such a test was cumbersome and operator-dependent and was supplanted by biochemical tests such as protein-bound iodine measurements initially in the 1950s, followed in the early 1970s by radioimmunoassay methods for measuring serum concentrations of T3, T4 and TSH [ 18 – 21 ]. Despite a historically late start in its recognition as a disease entity, hypothyroidism has remarkably become one of the most frequently diagnosed diseases in the Western world, and levothyroxine one of the most frequently used drugs worldwide [ 22 – 24 ]. How could a condition that had been overlooked throughout the centuries of human culture rise to such prominence in such a short time period? Clearly, this was related to the convenient and sensitive measurement of serum TSH [ 25 ], which has achieved a pre-eminent position in defining primary hypothyroidism [ 26 ]. Consequently, a new disease class of subclinical hypothyroidism was introduced, which is solely based on the presence of an elevated TSH while the thyroid hormones FT3 and FT4 remain within their respective reference ranges [ 26 ]. This strategy has not remained unchallenged and the deficiencies of this diagnostic approach have been reviewed elsewhere [ 27 ]. In an attempt to scale back on the avalanche of purported thyroid diseases created by this strategy, the TSH threshold for treatment was raised in recent guidelines [ 26 ]. In doing so, another problem was created by dissociating the TSH-based diagnosis of the disease from the requirement of therapeutic intervention. However, doctors and patients find it incomprehensible that a thyroid condition labelled as a disease would not therefore require suitable intervention. This questions the practical value of designation and appropriateness of the current diagnostic entity of subclinical hypothyroidism. Main text In this article, we take a closer look how these technical changes may have impacted on patient care. A transition occurred from the era of low metabolic rate regarded as synonymous with hypothyroidism to a purely biochemically based definition [ 28 ]. Hence, TSH measurement became the new determinant of hypothyroidism [ 26 ]. Consequently, treatment habits changed over the last decade and were more related to laboratory records than subjective patient experience. In particular, LT4 replacement doses tended to decrease, as a suppressed TSH was viewed as evidence of overtreatment [ 24 , 26 ]. However, for two reasons this is an area of considerable uncertainty. Firstly, thyroid-related patient complaints overlap with a plethora of non-specific symptoms caused by other conditions and diseases [ 29 – 36 ]. Thyroid tests are also more likely to be obtained in patients with unspecific symptoms [ 37 – 39 ]. In these conditions, LT4 treatment may not be superior to placebo in symptom alleviation [ 40 – 42 ]. Secondly, TSH is increasingly recognised to be less reliable as a definitive diagnostic tool than previously assumed [ 27 ]. Not only is its reference interval not universally agreed on or adjusted for various influences, such as ethnicity, iodine supply, age, but the univariate statistical derivation of a TSH reference range is inherently ill-defined owing to its nature as a controlling element [ 43 ]. Physiologically, stimulation by TSH raises thyroid hormones to a level appropriate to the optimal well-being of a person. Because TSH, FT4 and FT3 are interrelated through the operation of hypothalamic-pituitary-thyroid feedback regulation, integrated pairs of TSH and FT4 values define the so-called individual set points [ 43 , 44 ]. Unlike a population-based univariate reference interval, set points are subject to multivariate normality and narrow homeostatic ranges [ 43 ]. When plotting TSH against FT4 concentrations the resulting distribution in a healthy population does not describe the familiar rectangle, but a kite-shaped area [ 43 ]. Accordingly, a TSH value can be indicative of true euthyroidism in an individual despite it slightly exceeding the upper reference limit, while a TSH measurement within that reference interval may represent a truly hypothyroid subject [ 43 ]. Isolated TSH interpretation thereby becomes ambiguous, resulting in unacceptable diagnostic and therapeutic uncertainty surrounding a given TSH measurement when it approaches the TSH euthyroid range [ 43 , 44 ]. As a consequence, this strategy divorces diagnostic disease definitions from treatment targets. Rationally therefore, the triple roles of TSH as a screening test, diagnostic tool and therapeutic target require separate assessment. Diagnostic reliability for patients may be improved by reconstructing personal TSH-FT4 set points, depending on whether this novel approach can be confirmed in clinical trials [ 45 ]. Both the non-specific nature of complaints and inherent deficiencies in the diagnostic process raise an unsettling dilemma for patients and thyroid specialists alike. The issues are exemplified and particularly pertinent to an etiological disease entity whose consequences are paralleled in similar outcomes: primary hypothyroidism due to total thyroidectomy in patients with differentiated thyroid cancer. Treatment requirements and dosing of the drug LT4 changed when guidelines relaxed the need for TSH-suppressive treatment targets for these patients [ 46 , 47 ]. The reason for this shift was not primarily motivated by any improvement in the replacement strategy but by a revision of the long-held tenet that TSH may act as a thyroid growth stimulating hormone. Even when only present at a low level in the circulation it was believed that it could potentially stimulate the growth of remaining tumour cells and thereby promote the relapse of the thyroid cancer in the long-term [ 48 ]. This view has recently been revised, and TSH suppression is now deemed unnecessary for many thyroid cancer patients [ 49 ]. However, this remarkable strategy change has presented a unique opportunity to study the implications for patient complaints of such a far-reaching decision to abandon TSH-suppressive LT4 treatment in low-risk thyroid cancer [ 47 ]. Although this could not be done in a prospective study, careful retrospective analysis revealed some interesting trends [ 50 ]. Over the years when replacement therapy aimed at complete TSH suppression a relatively low rate of persistent hypothyroid complaints was reported by patients followed at a single institution, much lower than in the subsequent years when the relaxed TSH policy came into effect (Fig. ​(Fig.1).1 ). The reverse was true for hyperthyroid complaints reported by patients, which were relatively higher in the first and much lower in the second time period (Fig. ​(Fig.1).1 ). The symptom reporting by these patients indicates a historical shift in the trend from a lack of hypothyroid symptoms on LT4 towards an increased awareness of the persisting symptomatology. While the nature, reliability and accuracy of freely communicated symptoms may be questionable it appears that the opposing trends in these rates in the same patients are well documented in this cohort, and they occurred in association with an important change in the treatment policy during follow-up [ 46 – 50 ]. We are not aware of any prospective studies that followed this historic shift in the pattern of patient complaints during the last decade. The changing pattern in patient complaints observed in this cohort [ 50 ] and associated with the low-dose policy promoted by recent guidelines is mirrored in a recent prospective study [ 51 ] and by a dramatic increase in patients worldwide expressing their concerns and dissatisfaction with the standard treatment in various ways including over the internet and through patient advocacies [ 52 ]. This sentiment was confirmed by a large online survey of 12,146 hypothyroid patients conducted by the American Thyroid Association [ 11 ]. The expression of dissatisfaction may be partly explained by raised awareness of the problem, based on unspecific subjective criteria, and the possible contribution of a lack in certainty of the diagnostic process discussed above [ 11 , 29 – 45 ]. Patient expectations introduce a confounding influence on perceived outcomes [ 11 , 53 , 54 ]. This is difficult to address, particularly since expectation bias extends to RCTs, regarded as the highest class of evidence in Evidenced-Based Medicine [ 53 ]. A conflict arises between Evidenced-Based Medicine and FDA regulations, the latter mandating that drug evaluation is strictly done under conditions of actual use [ 53 , 55 ]. A statistical remedy (R2R) has been proposed to adjust for expectation bias, but we are not aware of any thyroid-related analysis following such a rigorous protocol [ 53 ]. A question may be asked as to why such a renunciation of a previous protocol has not been accompanied by the initiation of appropriate trials to monitor the consequences of the new recommendations and the transition period in a suitable way. We strongly believe that this should become a priority from a public health perspective and an important joint task of the stakeholders advocating for change in the best interest of patients. This would make any discussion surrounding this important topic better grounded in evidence. As most of our patients were otherwise healthy and free of comorbidity it does not seem to be plausible or fair to blame a host of other possible influences for their complaints [ 50 ]. Similarly, in patients with autoimmune thyroiditis, LT4 treatment did not restore quality of life assessed with a validated state-of-the-art and thyroid-specific instrument to that of the healthy population in a large Danish open label study [ 51 ]. It remains however questionable whether these patients received optimum treatment, since some patients did not have their TSH “normalised” and the pituitary hormone may also be an unreliable marker in this particular setting [ 51 ]. Using the observed historical narrower therapeutic range for an individual patient we note that the treatment targets may overlap for patients in a group. If that is true the general assumption that maintaining TSH anywhere within its broad reference limits to routinely achieve a satisfactory outcome for each and every patient may be ill advised. We have refuted the applicability of treatment targets based on the consideration of the reference ranges in the healthy population, by demonstrating dissociations between FT3 and FT4, and FT3 and TSH in LT4-treated athyreotic patients, and documenting altered equilibria between the hormones on LT4, compared to the healthy state [ 27 , 56 ]. Others have arrived at similar conclusions [ 57 ]. In laboratory diagnostics, the high individuality of TSH and thyroid hormones has long been recognised since the pioneering work of Andersen and colleagues [ 58 ]. However, this applies equally to the statistical analysis of associations involving thyroid parameters. Data clustering, be it in groups with similar properties or in subjects where multiple measurements are obtained over time, potentially masks the true relationship, abolishing the strong associations at the group level when the data are combined for analysis. This phenomenon, known as Simpson’s paradox, is readily demonstrated with a fictitious random sample of two groups with a slightly shifted centre showing the same strong inverse correlation. Unlike the correct analysis by individual groups, a combined analysis of the total cohort artificially weakens the correlation (Fig. ​(Fig.2).2 ). The analytical distinction between the averaged versus the typical outcome is clinically relevant for all thyroid drug trials, independently of evidence class and study design, because doctors are naturally more interested in the latter. In a large retrospective longitudinal study, relying on a multilevel model and accounting for both within-subject and between-subject variation, symptomatic outcomes were associated with serum FT3 concentrations, and differed according to the placement of biochemical parameters within the reference range or noticeably beyond its limits in the case of TSH and FT4 [ 50 ]. Treatment-related displacement of the equilibria between thyroid parameters, wide variations in the biochemical treatment response, and individually adjusted dose requirement pose particular challenges for thyroid trials [ 27 , 45 , 59 , 60 ]. Demonstration of averaged equivalency cannot therefore be a satisfactory analytical goal [ 61 ]. Accordingly, the value of statistical evidence derived from historical meta-analyses [ 62 – 66 ] and RCTs on the acceptability of T3/T4 combination therapy is severely weakened and requires careful reconsideration [ 60 ]. Many RCTs were conducted with inferior quality of life instruments available at the time and relied on statistical techniques both less suited for highly individual parameters and in addition susceptible to Simpson’s paradox. Using the overall preference expressed by patients at the end of double-blind studies as a proxy, patients mostly favoured T3/T4 combination therapy [ 52 ]. A thyroid-specific QoL has only recently been developed and validated [ 51 ]. Simpson’s paradox (also known as amalgamation bias or collider stratification bias) may explain, at least in part, why otherwise well-performed studies failed to provide a convincing relationship between symptoms and thyroid function tests [ 27 , 54 , 59 – 61 ]. The paradox is a relevant factor for the relationship of patient complaints, biochemical markers and treatment response to LT4 [ 60 ]. This bias - unless properly accounted for statistically - dissociates the personal treatment responses from the statistical group effect, thereby masking individual treatment success or failure in an unchanged grouped outcome. A lack of group to individual generalizability has been increasingly recognized in other fields, requiring explicit testing for equivalence of processes both at the individual and group level [ 61 ]. Trials purporting to relate TSH and thyroid hormone levels to the incidence of osteoporosis and atrial fibrillation fall under the same fundamental caveats [ 24 , 27 ]. In particular, the Rotterdam study has shown that within the euthyroid range the prognostic implications of thyroid hormones and TSH differ, and, that TSH measurements therefore cannot substitute for FT4 concentrations in predicting the risk of atrial fibrillation [ 67 ]. The cause of atrial fibrillation poses a complex problem, as its occurrence has been physiologically and statistically associated with both high and low FT3 concentrations [ 68 ]. Thyrotoxicosis due to exogenous thyroid hormone intake and endogenous hyperthyroidism have different physiological roots. This traditional distinction should be noted because the interrelationships between TSH and thyroid hormones differ on LT4 treatment from those in thyroid health [ 24 , 56 , 57 , 59 , 69 ]. This may explain why a prospective study measuring surrogate markers of thyroid tissue effects in athyreotic patients found a slightly suppressed TSH to be optimum for these patients rather than constituting overtreatment [ 57 ]. This problem is paralleled in FT4 measurements, which also overlap significantly at the hypothyroid-euthyroid borderline, both in untreated states and even more so in LT4-treated patients [ 24 , 26 , 59 , 67 ]. However, this neither implies that TSH suppression is universally desirable, nor that a suppressed TSH is without risk [ 24 ]. Rather TSH by itself, unaccompanied by measurements of FT4 and FT3, is an unsuitable risk measure in LT4-treated patients, displaying considerable inherent uncertainty in an individual about the risk - benefit ratio for TSH values close to the lower reference limit [ 27 , 69 ]. Taken together, a combination of nonspecific complaints, statistical group-to-individual bias and limited diagnostic performance of TSH testing obfuscates the transition between diseased and healthy state and fosters disagreement of interpretation depending on the respective focal points. Serious correction of scientific evidence is not unprecedented in medicine. Notably, some cholesterol trials have undergone re-interpretation, reversing previous conclusions, following re-analysis of recovered crude data with improved statistical methods [ 70 ]. Market retraction of the antidiabetic drug rosiglitazone is just one noteworthy example of an initially overlooked effect reversion due to Simpson’s paradox [ 71 ]. New studies could be performed in the light of changes in the treatment habits, consequential shifts in symptom reporting and the complaint spectrum as well as recent developments in statistical analysis which favour greater stratification of disease aetiology and individual outcome before commencing suitable analytic procedures. Emphasis should be more strongly concentrated on personalised treatment strategies, reflected by appropriate protocols and statistical instruments favouring multilevel analysis or latent class hierarchical models. Range-based use of biochemical thyroid parameters, though having an essential role in diagnosis, should not automatically dominate patient presentation and surrogate markers for tissue T3 effects [ 26 , 57 , 60 , 72 , 73 ]. When rejecting patient preference as an objective criterion, standard LT4 and combination therapy performed equally on average on QoL measures in several metanalyses [ 62 – 66 ]. However, heterogeneity of the observed treatment response and collider stratification bias require targeting homogenous subgroups and performing statistical latent class analysis [ 60 , 61 ]. This may identify patients that preferentially benefit from the two modalities [ 60 ]. TSH and FT3 dissociate under LT4 treatment, particularly in athyreotic patients where equilibria are formed between TSH and FT4/FT3 different from the healthy state [ 56 , 57 , 59 ]. Poor T3 converters with persisting symptoms may thus be the most suitable candidates for trials of T3/T4 combinations. T3 addition may also avoid LT4 dose escalation resulting in T4 excess, as T4 has been implicated in non-genomic actions, not mediated via T3, such as actin-related cell migration [ 74 ]. Following the timeless wise words of Paracelsus “Dosis solum facit venenum” (“Only the dose makes the poison”). and in keeping with the historic practice to adjust LT4 dose based on a metabolic marker, individual dosing regimens and personalised treatment targets have to be reconsidered [ 27 ]. This is another area where current TSH based LT4 dosing guidelines fall short, as carefully conducted experiments in rodents, which cannot be performed in humans, have shown [ 72 , 73 ]. LT4 monotherapy was unable to restore euthyroidism at the level of various tissues in the animals despite bringing TSH within its reference range [ 72 , 73 ]. Conclusions Until the situation is clarified all currently available treatment options should remain on the table and the focus should remain on facilitating the free choice of prescriptible treatment options rather than imposing new restrictions. The biochemically based reason for the rise in patient complaints has to be addressed, not a shift on to them of blame and burden of proof. This invites a resume of the current state of affairs. It appears that what we are witnessing constitutes an unprecedented historic change in the diagnosis and treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH and supported by persuasive guidelines. This has resulted in a mass experiment in disease definition and a massive swing of the pendulum from a fear of drug-induced thyrotoxicosis to the new actuality of unresolved designation of hypothyroidism. All of this has occurred in a relatively short period of time without any epidemiological monitoring of the situation. Evidence has become ephemeral and many recommendations lag behind the changing demographic patterns addressing issues that are no longer of high priority as the pendulum has already moved in the opposite direction. 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Written by: Berenike Rogge , Marcus Heldmann , Krishna Chatterjee , Carla Moran , Martin Göttlich , Jan Uter , Tobias A. Wagner-Altendorf , Julia Steinhardt , Georg Brabant , Thomas F. Münte  & Anna Cirkel   Thyroid Research volume 16 , Article number: 34 (2023) Abstract Background Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. Methods High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). Results RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. Conclusion RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined. Introduction Thyroid hormone levels and transporter proteins influence the development of the human brain. Brain development is mediated by thyroid hormone action [ 1 ]. Irregularities in balance of thyroid hormones at precise developmental timings can lead to somatic and cognitive changes [ 2 ]. We have previously shown that a period of only several weeks duration of induced hyper- or hypothyroid states influences the function and structure of the brain, without significant measurable somatic changes in parameters such as heartrate or blood pressure [ 3 , 4 , 5 , 6 ]. Moreover, hypothyroidism during adulthood induces morphological changes in the brain [ 7 ]. Thyroid hormones regulate developmental and physiological processes, acting via nuclear, thyroid hormone receptors (TRa, TRb), to alter transcription of target genes. Mutations in receptor genes ( THRB and THRA ), cause syndromes of Resistance to Thyroid hormone (RTHb, RTHa) [ 8 , 9 ], whose phenotypes differ due to the differential expression of TR isoforms in tissues (TRα1: central nervous system, myocardium, skeletal muscle, bone and gastrointestinal tract; TRβ1: liver, kidney; TRβ2: hypothalamus, pituitary, cochlea, retina) [ 10 ]. RTHβ, due to heterozygous mutations in THRB , is a relatively uncommon disorder with over 800 families with 200 different receptor mutations being recorded to date [ 11 ]. Due to impaired function of the TRβ2 isoform expressed in the hypothalamus and pituitary [ 12 ], normal negative feedback regulation of TSH by thyroid hormones is perturbed, resulting in raised circulating free thyroid hormones (fT4, fT3) with non-suppressed TSH concentrations [ 10 ]. Due to differential distribution of TR subtypes, RTHβ patients exhibit symptoms reflecting hypo- and hyperthyroid states of specific tissues [ 10 ]. Typical phenotypes in RTHβ include goiter, resting tachycardia, recurrent ear infections in childhood causing hearing loss, altered photoreceptor function and attention-deficit hyperactivity disorder (ADHD) [ 13 , 14 , 15 ]. Indeed, previous studies suggest that ADHD is the main neurocognitive abnormality in RTHβ, with approximately half of RTHβ patients exhibiting an ADHD-like phenotype [ 16 , 17 , 18 , 19 ]. The differential tissue distribution of TRs suggests that RTHß patients might show abnormalities in brain structure, which, in turn, might be related to behavioural changes. Accordingly, in this study, changes in grey matter volume using voxel based morphometry, were analyzed [ 20 , 21 ]. Previous studies of patients in hyper- or hypothyroid states [ 3 , 7 , 22 , 23 ], have revealed structural changes, suggesting that this method would also reveal changes in RTHß. Measurement of cortical thickness has also highlighted structural changes in thyroid disease [ 24 , 25 ]. An earlier publication had suggested that male RTHb patients exhibit multiple Heschl’s transverse gyri in the primary auditory cortex [ 26 ], so we sought to verify these findings in the current study. Thyroid hormones have been shown to regulate myelination of neurons [ 1 ]. Such changes in myelination in brain white matter are reflected in different parameters gleaned from diffusion tensor imaging (DTI). For example, reductions of fractional anisotropy (FA) have been found in hypothyroid patients in the corticospinal tract, the posterior limb of the internal capsule, uncinate fasciculus, and inferior longitudinal fasciculus [ 27 ]. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. Materials and methods Subjects In total forty-two subjects were recruited; twenty-one RTHβ subjects (mean age 39 y, SD 15.0, 12 women) were matched with 21 healthy controls (mean age 38 y, SD 14.0, 12 women, from Lübeck, Germany). The participants in this study are unselected cases of RTHb, diagnosed in Cambridge following referral to this centre for investigation of discordant thyroid function (raised thyroid hormones, non-suppressed TSH). The investigation of all participants took place at the University Medical Centre Schleswig-Holstein, Campus Lübeck, Germany. The patients carried the following heterozygous TRß mutations: R320H (n = 5), R438H (n = 4), R429Q (n = 3), R383C (n = 2), M310V (n = 1), G345C (n = 1), P453S (n = 1), R243W (n = 1), T277I (n = 1), R338W (n = 1), E460K (n = 1). Mutations were maternally (n = 12) or paternally (n = 3) inherited or occurred de novo  (n = 6). Medication in single patients included thyroxine for coincident autoimmune hypothyroidism (n = 1), propranolol in reduced dosage at initial referral, alfacalcidol for postsurgical hypoparathyroidism and atenolol for high blood pressure. All patients were screened for general health, drug abuse and medical comorbidities, with evaluation of thyroid status (TSH, fT4, fT3), and fasting lipid profiles (Total, LDL and HDL cholesterol). All patients were examined by an endocrinologist. Their structural brain images were evaluated and approved to be normal by a neuroradiologist. All subjects were right-handed. Blood parameters were analysed on serum (transported at minus 80) in Cambridge with TSH, fT3 and fT4 being measured by Advia Centaur (Siemens) as described previously [ 28 ]. The reference ranges of hormone measurements were as follows: fT3 3.5–6.5 pmol/l, fT4 10–19.8 pmol/l and TSH 0.35–5.5 mU/l. Attention deficit analysis We used the Adult ADHD Self-Report Scale  (ASRS-v1.1) [ 29 ], composed of 18 questions describing typical symptoms of ADHD consistent with the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The test asks for typical symptoms (i.e. deficits in attention, concentration), impairments (i.e. at work, school or in family settings) and history (i.e. were the symptoms also present in childhood). Additionally, the ADHD Rating Scale-IV  was used, consisting of two subscales including 9 items scaling inattention and 9 items regarding hyperactivity impulsivity [ 29 ]. To test for group differences independent t-test per ADHD Rating Scale-IV  subscales will be used. MRI data acquisition and analysis Structural MR imaging was performed at the CBBM Core Facility Magnetic Resonance Imaging using a 3-T Siemens Magnetom Skyra scanner equipped with a 64-channel head-coil. Structural images of the whole brain were recorded using a 3D T1-weighted MP-RAGE sequences were acquired (TR = 1900 ms; TE = 2.44 ms; TI = 900 ms; flip angle 9°; 1 × 1 × 1 mm3 resolution; 192 × 256 × 256 mm3 field of view; acquisition time 4.5 min). Diffusion-weighted data were recorded using a 64-direction DTI sequence (Single-Shot EPI sequence, 70 slices, TR = 6100 ms, TE = 116 ms, FOV 244 × 244 mm2, voxel size 1 × 1 × 2 mm3, flip angle 90, b-value 1500 s/mm2, one b0 (without diffusion weighting) image at the beginning and 4 b-zero images at the end of the sequence). Analysis was corrected for age and gender. Diffusion tensor imaging Diffusion tensor imaging (DTI) is an imaging technique enabling to non-invasively measure white matter changes in the central nervous system. Preprocessing including eddy correction and rotation of the vector definitions was performed using the FMRIB Software Library [ 30 ]. The resulting tensor images were transformed to DTI-ToolKit data format ( http://www.nitrc.org/projects/dtitk/ ) and registered to the IIT tensor template provided by the IIT atlas [ 31 ] combining rigid, affine, and diffeomorphic registration steps. Based on the spatially normalized tensor images DTI-ToolKit was also taken to calculate individual FA maps. To test for group differences SPM12 toolbox was used to perform a two-sample t-test with age as covariate. Statistic images were assessed for cluster-wise significance using a cluster-defining threshold of P = 0.001; the 0.05 FWE-corrected critical cluster size was 275. Voxel based morphometry Voxel-based morphometry (VBM) is a technique to analyses structural changes of the brains grey matter using T1-weighted MR images. It measures differences of grey matter by a voxel-wise comparison of multiple brain images. VBM analysis was evaluated in the whole brain, carried out using Statistical Parametric Mapping 12b (SPM, http://www.fil.ion.ucl.ac.uk/spm ) and Computational Anatomy Toolbox ( http://www.neuro.uni-jena.de/cat/ ; version 12.6, 1445) in Matlab R2019b. Preprocessing of the data comprised tissue segmentation and spatial registration using DARTEL, removal of inhomogeneities and noise, global intensity normalization and spatial smoothing (12 mm FWHM Gaussian Kernel). Total intracranial volume (TIV) was also calculated. After preprocessing a two-sample t-test was computed as group statistic for every voxel, whereby age and intracranial volume were considered as confounding factors. Since we found no significant differences when applying a correction for multiple testing, we considered the results also at an uncorrected p-value of 0.001, which is a common method to explore patient data. Due to an increase of the alpha error it has to be acknowledged, though, that this approach may produce false positive results. Cortical thickness Cortical thickness analysis measures the width of grey matter in the human cortex. The analysis of cortical thickness was also performed with SPM12 and the CAT toolbox using the algorithm described by Dahnke et al. [ 32 ]. Based on the VBM preprocessing steps the central surface and the cortical thickness was estimated using a projection based thickness approach [ 32 ]. Initial surface reconstruction was followed by repair of topological defects and surface refinement resulting in the final central mesh [ 33 ]. For statistical analysis we followed the program’s recommendation using a 15 mm FWHM Gaussian kernel for spatial smoothing. We calculated a two-sample t-test with age as covariate. To correct for multiple comparisons at cluster level = 633 a threshold of p = 0.05 (FWEc) and a cluster defining threshold of p = 0.001 was applied. Relationship brain structure and attention deficit To test for a correlational relationship between structural changes and Attention deficit test scores regions of interest (ROIs) will be defined by the clusters resulting from the group comparisons. Mean FA and VBM scores extracted from these clusters will be correlated with test scores which also show a significant difference between groups. Since CAT toolbox does not allow for the individual definition of ROIs mean values will be extracted from the atlas definition in which the significant group difference was observed. The atlas definition used here was the Desikan-Killiany Atlas. Correlations were calculated using spearman’s rho. Since the correlational analysis was exploratory we did not correct for multiple comparisons. Analysis of Heschl’s gyri The sizes of Heschl’s gyri were measured manually, the brain region was selected by specialists voxel by voxel. The program mricron ( https://www.nitrc.org/projects/mricron  [ 34 ] was used to define the region layer-by-layer with manual tracing using a mouse-guided cursor. Heschl’s gyri analysis was performed in a blinded fashion, first in independent sessions, followed by a subsequent combined session by two different examiners (one neurologist, one neuroscientist). In line with previous reports number of Heschl’s gyri was classified into typical (one gyrus) and atypical (multiple gyri) [ 26 , 35 , 36 ]. Prior to performing the analyses, the examiners agreed to the procedures during a joint session using sample brain images. Differences between the number of typical and atypical Heschl’s gyri were statistically tested using a chi squared test. Results Circulating thyroid hormone concentrations Mean TSH was shown to be within the normal range in both RTHβ patients and control subjects. Both fT4 (RTHβ: Mean 28.4 pmol/L, SD 5.5 pmol/L. Controls: Mean: 14.6 pmol/L, 1.6 pmol/L. P < 0.001, two-sample t-test) and fT3 (RTHβ: Mean 8.6 pmol/L, SD 1.6 pmol/L. Controls: 5.1 pmol/L, SD 0.5 pmol/L. P < 0.001, two-sample t-test) concentrations were significantly elevated in RTHβ patients, but were within the normal range in control subjects. Clinical symptoms All subjects were examined by an endocrinologist and a neurologist with additional training in psychiatry. Out of the 21 RTHβ patients, one showed tachycardia, whereas eleven reported occasional palpitations. In the clinical history, 9 patients reported difficulties in concentrating and 12 reported anxiety episodes. Other signs and symptoms of hyperthyroidism (increased perspiration, peripheral tremor, proximal myopathy, increased stool frequency, weight loss, changes in menstrual cycle) were not present. None of the patients exhibited features of hypothyroidism (e.g. cold intolerance, constipation, weight gain, dry skin, hair loss, bradycardia, delayed relaxation of tendon reflexes, carpal tunnel syndrome). Attention deficit analysis The self-rating questionnaires for ADHD I and II revealed significantly higher scores in the RTHβ group (ADHD I mean = 95.7 (9.1), ADHD II mean = 36.1 (2.3)) in comparison to controls (ADHD I mean = 60.6 (4.8), ADHD II mean = 24.1 (1.7); ADHD I: RTHβ vs. controls t(36)=|3.31|, p = 0.002; ADHD II: RTHβ vs. controls t(36)=|4.16|, p = 0.0018). Imaging results Tractography via diffusion tensor imaging (DTI) revealed significantly higher FA in the corticospinal tract (CST) in RTHß patients (FWEc 0.05, k = 275) (see Fig.  1 ; Table  1  A). In the RTHβ group, superior parietal cortical thickness was increased bilaterally (FWE(p < 0.05), k = 587) (see Fig.  2  and Table  1 B). Voxel-based morphometry (VBM) revealed decreased grey matter volume (GMV) bilaterally in the inferior temporal cortex and the thalamus and in the right superior frontal orbital gyrus in RTHβ subjects. Increase in GMV was shown in left precuneus and right middle frontal gyrus in RTHβ subjects. VBM results were based on an uncorrected level (p[unc.] = 0.001, k = 100) (see Fig.  3 ; Table  1  C). Analysis of Heschl’s gyri showed no statistical difference when comparing patients and controls (Chi2(2) = 4.40; p = 0.11). Similar to published literature [ 26 ], we also checked for gender differences in this structural parameter, finding that women in the RTHβ-group had multiple Heschl’s gyri less often than female controls (Chi2(2) = 7.6, p = 0.02, see Table  2 ); for men there was no significant difference in Heschl’s gyri (Chi2(2) = 0.47, p = 0.78). Relationship brain structure and attention deficit analysis With regard to VBM analyses the cluster located in the right midfrontal cortex was significantly correlated with ADHD I (rho = 0.66, p = 0.002) and ADHD II (rho = 0.58, p = 0.009) scores in the RTHβ-group, whereas the control group showed no significant correlation. Furthermore, in the RTHβ-group, decreases in FA values in the right CST were marginally correlated with the ADHD I (rho=-0.4, p = 0.091) and ADHD II (rho = 0.41, p = 0.083) scores. In contrast, FA values in the left CST were positively correlated with ADHD II scores (rho = 0.43, p = 0.046) in the control group (see Fig.  4 ). Analysis of the cortical thickness ROIs revealed no significant relationship. Discussion As anticipated, RTHß patients showed significant differences in both grey and white matter compared to normal control participants and these changes will be considered in further detail as follows. Diffusion tensor imaging showed that FA in the corticospinal tract differed in RTHß versus control subjects. The corticospinal tract supports motor control of the spinal cord and voluntary movement [ 37 ]. It is known that thyroid hormones regulate myelin formation [ 1 ], therefore it can be speculated that a changed FA in RTHß can be due to their local hyperthyroid state in the brain influencing white matter tissue and myelin formation. However, the functional relevance of these changes in the corticospinal tract remains to be explored using (for example) transcranial magnetic stimulation and sensitive measures of motor performance. Changes in white matter have been recorded in hyperthyroid patients with thyroid opthalmopathy [ 38 ] and also in patients with Resistance to Thyroid Hormone due to mutations in TRa [ 39 ]. Thus, more studies are needed to explore the influence of TH on brain white matter. Voxel based morphometry revealed a decrease of grey matter volume bilaterally in the inferior temporal cortex and the thalamus. The thalamus is a key relay hub, making multiple connections to cortical and subcortical regions. It is also known to play an important role in selective attention, visual and auditory information [ 40 ]. The functional significance of these thalamic changes remains to be explored. The temporal lobe and its associated networks are involved in multiple cognitive domains, including auditory, vision, language, memory, and semantic processing [ 41 ]. This structural observation is particularly interesting, since our RTHß patients showed an ADHD-like phenotype, which characteristically involves neuropsychological deficits. In addition, heterozygous RTHb patients exhibit altered retinal photoreceptor function and sensitivity of color perception [ 15 ], and this may correlate with the fact that the inferior temporal cortex plays a key part in the visual pathway, including color perception [ 42 ]. In a previous study [ 3 ] we have analyzed healthy participants with experimentally-induced thyrotoxicosis, revealing an increase of grey matter volume in the posterior part of the cerebellum and a decrease of grey matter volume in the anterior part of the cerebellum. While these observations clearly differ from findings in this study, it has to be kept in mind that the effects of biochemical hyperthyroidism in RTHß patients may be more complex, depending on whether particular brain regions are in a relatively hypothyroid or hyperthyroid state, depending on whether they express mutant TRß or normal TRα. Experimentally-induced thyrotoxicosis also leads to an increased connectivity in temporal lobe structures, caused by an increased connectivity to the cognitive control network [ 43 ]. Such increased connectivity supports a role for thyroid hormones in regulating paralimbic structures, with increased degree centrality in the temporal pole being correlated with changes in observed depression scores [ 43 ]. This may facilitate prefrontal control over limbic areas, possibly explaining the successful use of thyroid hormones as an augmentation therapy for depression. Heschl’s gyrus analysis  showed no difference among groups regarding number of gyri. Whereas one previous study had shown an increased number of gyri in RTHß men [ 26 ], this was not replicated by our results. Instead, we found less multiple Heschl’s gyri in RTHß women. We conclude that there is no substantial influence of RTHß on Heschl’s gyrus morphology in our cohort of patients. Cortical Thickness  was increased in superior parietal cortex bilaterally in the RTHß group. It is well-known that the parietal cortex is involved in sensory, motor, and cognitive functions, especially regarding space-based and feature-based attention functions and working memory [ 44 ]. The parietal cortex is involved in the attention network, parietal cortices generate attention-related modulatory signals and parietal lesions can lead to profound attentional deficits, including visuo-spatial neglect, hereby preventing directing attention contralesionally [ 45 ]. ADHD is known to be associated with impairments in attention and with changes in fronto-parietal networks [ 46 ], which is relevant because RTHß patients, including participants in the current study, exhibit an ADHD-like phenotype [ 16 , 17 , 18 , 19 ]. Indeed, increased parietal cortical thickness has also been shown in adult subjects with conventional ADHD [ 47 , 48 ] whereas reduced cortical thickness was seen in children and adolescents with ADHD [ 49 , 50 , 51 ]. Since our study has documented increased parietal cortical thickness in RTHb, it is tempting to postulate that this structural change may be linked to attentional deficits and ADHD-like phenotype in the disorder. With the knowledge that hypothyroidism during development can also affect cortical thickness in various brain regions [ 25 ], it is conceivable that resistance to thyroid hormone action which is also a relative hypothyroid state, could have contributed to this morphological change. Limitations of our study include the relatively small sample size and thus reduced power to detect subtle changes in brain structure. Additionally, the study population was heterogeneous, as RTHb patients from UK were matched with healthy controls from Germany, with a possibility of confounding due to socio-economic and educational differences between the two groups. Nevertheless, we maintain that our study contributes new knowledge about brain structure in this disorder. 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Written by Theodore T Zava  & David T Zava   Thyroid Research volume 4 , Article number: 14 (2011) Abstract Japanese iodine intake from edible seaweeds is amongst the highest in the world. Predicting the type and amount of seaweed the Japanese consume is difficult due to day-to-day meal variation and dietary differences between generations and regions. In addition, iodine content varies considerably between seaweed species, with cooking and/or processing having an influence on iodine content. Due to all these factors, researchers frequently overestimate, or underestimate, Japanese iodine intake from seaweeds, which results in misleading and potentially dangerous diet and supplementation recommendations for people aiming to achieve the same health benefits seen by the Japanese. By combining information from dietary records, food surveys, urine iodine analysis (both spot and 24-hour samples) and seaweed iodine content, we estimate that the Japanese iodine intake--largely from seaweeds--averages 1,000-3,000 μg/day (1-3 mg/day). Introduction Japanese iodine intake exceeds that of most other countries, primarily due to substantial seaweed consumption. Iodine is an essential element required for thyroid hormone synthesis, believed to impart some of its antioxidant and antiproliferative activity in the prevention of cardiovascular disease and cancer [ 1 – 8 ]. Seaweeds have the unique ability to concentrate iodine from the ocean, with certain types of brown seaweed accumulating over 30,000 times the iodine concentration of seawater [ 9 ]. The amount of iodine the Japanese consume daily from seaweeds has previously been estimated as high as 13.5 to 45 mg/day by sources that use ambiguous data to approximate intake [ 10 , 11 ], an amount 4.5 to 15 times greater than the safe upper limit of 3 mg/day set by the Ministry of Health, Labor and Welfare in Japan [ 12 ]. While high iodine intake from seaweed consumption is believed to have numerous health benefits, it has been reported to negatively affect individuals with underlying thyroid disorders [ 13 – 16 ]. To prevent excessive consumption it is imperative for people seeking health benefits from a high iodine diet to be knowledgeable of the amount of iodine the Japanese consume daily. In this paper we use a combination of dietary records, food surveys, urine iodine analysis, and seaweed iodine content to provide a reliable estimate of Japanese iodine intake, primarily from seaweeds. Types of edible seaweeds and their iodine content In Japan, over 20 species of red, green, and brown algae (seaweed) are included in meals [ 17 ]. Iodine content varies depending on species, harvest location and preparation, and is typically highest in fresh cut blades and lowest in sun bleached blades [ 18 ]. The three most popular seaweed products in Japan are nori ( Porphyra ), wakame ( Undaria ) and kombu ( Laminaria ). Dried iodine contents range from 16 μg/g in nori to over 8,000 μg/g in kelp flakes; Japanese kombu and wakame contain an estimated 2353 μg/g and 42 μg/g respectively [ 18 , 19 ]. Ten different species of Laminaria , a type of kelp commonly labeled as kombu, from around the world were examined for their iodine content and were found to average 1,542 μg/g when dried [ 17 ]. Japanese seaweed consumption statistics As the Japanese transitioned from a traditional to a Westernized diet, beginning around the 1950's [ 20 ], consumption of certain seaweed species declined while others increased. A decrease in kombu consumption (844 to 685 g/year per household) and an increase in wakame consumption (727 to 1234 g/year per household) can be seen between the years of 1963 and 1973 [ 21 ]. Consumption of kombu per Japanese household dropped further to 450 g in 2006 (elders ate up to four times more than those under the age of 29) [ 19 ]. Since daily seaweed consumption per person in Japan has remained relatively consistent over the last 40 years (4.3 g/day in 1955 and 5.3 g/day in 1995) [ 22 ], it is believed that consumption of wakame and nori have made up for the decline in kombu consumption [ 23 , 24 ]. Both nori and wakame have relatively low iodine contents compared to kombu. Seaweed consumption frequency differs from person to person in Japan, resulting in a constantly fluctuating iodine intake. Seaweed is served in approximately 21% of Japanese meals [ 25 ] with 20-38% of the Japanese male and female population aged 40-79 years consuming seaweed more than five times per week, 29-35% three to four times per week, 25-35% one to two times per week, 6-13% one to two times per month, and 1-2% rarely consuming seaweed [ 26 ]. A 2010 food frequency questionnaire on the Japanese Kombu Association website indicates that kelp (assuming kombu) is consumed at a rate of: 27.5% once per week, 25.5% once per month, 18% three or four times per week, and 15.9% once every few months, with only 6.1% of survey respondents stating they consume kelp nearly every day [ 27 ]. Effect of cooking on seaweed iodine content Seaweed is often cooked to flavor dishes or soup stocks before consumption. When kombu is boiled in water for 15 minutes it can lose up to 99% of its iodine content, while iodine in sargassum, a similar brown seaweed, loses around 40% [ 28 , 29 ]. Processed kelp is often boiled in dye for half an hour ("ao-kombu" or "kizami-kombu") before hanging to dry [ 21 ], a process which can reduce seaweed iodine content before it is consumed. When kelp is used to flavor soup stocks the seaweed is often removed after boiling, resulting in soup stock high in iodine. Twenty samples of supermarket soups with kelp or kelp broth were analyzed by Nishiyama et al. to determine iodine content, revealing a minimum concentration of 660 μg/L (0.66 mg/L) and a maximum concentration of 31,000 μg/L (31 mg/L) [ 16 ]. Serving size for soup is typically around 0.25 L, resulting in 165 to 7,750 μg (0.165 to 7.75 mg) of iodine per serving. Estimating Japanese iodine intake from seaweed consumption Due to variation of iodine content from one seaweed species to the next, along with confusion stemming from wet and dry weight terminology, many inaccurate assumptions have been made regarding the amount of iodine the Japanese actually consume from seaweed. Not all studies, dietary records or surveys specify whether daily or yearly consumption of seaweeds is recorded using wet weight, dry weight or a combination of the two. In some reports seaweed consumption has been estimated at 4-7 g/day dried weight [ 17 , 22 , 30 , 31 ], while other reports claim consumption of 12 g/day using both wet and dry weight  [ 32 ]. Certain seaweeds have a swelling capacity of nearly ten times their dry volume with moisture content typically over 70% when wet and around 7-20% when dried [ 33 , 34 ]. The difference between wet and dry weight, along with the type of seaweeds being consumed, can result in extreme overestimation (more likely) or underestimation (less likely) of Japanese iodine intake. Interpreting information to determine Japanese seaweed consumption and resulting iodine intake is a difficult task, and with ever changing diets, a close estimate is all that can be made. Nori and wakame are the most commonly consumed seaweeds in Japan, with nori accounting for 45% and wakame accounting for 30% (75% together) of total seaweed consumption, as stated by the Food and Agriculture Organization of the United Nations [ 35 ]. Based on previous estimates and records, dried seaweed consumption of 4-7 g/day [ 17 , 22 , 30 , 31 ] results in iodine intakes between 79 and 139 μg/day from nori and wakame when calculated using dried iodine contents of 16 and 42 μg/g respectively [ 18 ]. The remainder of iodine intake is derived mainly from kombu consumption, with smaller amounts coming from other seaweeds that have nominal iodine content. Kombu has the highest iodine content of all seaweeds in the Japanese diet. In 2006 consumption of kombu/household/year was 450 g [ 19 ], and with an average of 2.55 members per household in Japan in 2005 [ 36 ], 0.48 g kombu/person/day was consumed. When calculated, 0.48 g of kombu with an iodine content of 2,353 μg/g [ 18 ] equates to 1,129 μg/day of iodine. Assuming negligible iodine intake from the other seaweeds consumed, daily iodine intake from nori, wakame, and kelp can be estimated at 1,208 to 1,268 μg/day (1.2 to 1.3 mg/day). It is reasonable to assume that iodine intake per day based on seaweed consumption frequency and iodine content averages around 1,000-2,000 μg/day (1-2 mg/day). Estimating Japanese iodine intake from diet studies and urine iodine analysis Seaweed consumption statistics only provide only an estimate of Japanese iodine intake and should be combined with other predictive factors. Fortunately, studies that measure iodine content of single or entire meals are available and are, arguably, the most accurate estimate of Japanese iodine intake from seaweeds. A collection of Japanese diet studies that measure the amount of iodine in 24-hour diet samples or single meals can be seen in Table 1 . Daily iodine intake of the Japanese based on 24-hour diet samples generally does not exceed 3,000 μg (3 mg). Because approximately 97% of dietary iodine is excreted in the urine, urine iodine levels taken from individuals or populations can provide a secondary estimate of Japanese iodine intake from seaweed consumption, when paired with diet studies [ 37 , 38 ]. Urine iodine levels can increase from 100 μg/L to 30,000 μg/L in a single day and return to 100 μg/L within a couple of days, depending on seaweed intake [ 39 ]. This is somewhat expected when varying amounts and types of seaweeds are consumed on a day-to-day basis. Urine creatinine levels seen as μg iodine/g creatinine ( μg/g Cr) can be used to adjust for an individual's hydration status, correlating well with μg/L in areas of adequate nutrition [ 40 ]. Urine iodine levels of the Japanese found in a number of studies are shown in Table 2 . Mean and median iodine levels in the Japanese urine collections typically do not exceed 3,000 μg/L (3 mg/L). When using 1.5 L as an expected 24-hour urine output, urine iodine excretion should rarely exceed an estimated 4,500 μg/24 hr (4.5 mg/24 hr). Japanese health statistics linked to high seaweed intake The Japanese are considered one of the world's longest living people, with an extraordinarily low rate of certain types of cancer. A major dietary difference that sets Japan apart from other countries is high iodine intake, with seaweeds the most common source. Here are some astonishing Japanese health statistics, which are possibly related to their high seaweed consumption and iodine intake: Japanese average life expectancy (83 years) is five years longer than US average life expectancy (78 years) [ 41 ]. In 1999 the age-adjusted breast cancer mortality rate was three times higher in the US than in Japan [ 42 ]. Ten years after arriving in the US (in 1991), the breast cancer incidence rate of immigrants from Japan increased from 20 per 100,000 to 30 per 100,000 [ 43 ]. In 2002 the age-adjusted rate of prostate cancer in Japan was 12.6 per 100,000, while the US rate was almost ten times as high [ 44 ]. Heart related deaths in men and women aged 35-74 years are much higher in the US (1,415 per 100,000) as they are in Japan (897 per 100,000) [ 45 ]. In 2004, infant deaths were over twice as high in the US (6.8 per 1,000) as they were in Japan (2.8 per 1,000) [ 46 ]. Negative effects of iodine from seaweed High iodine intake from seaweed consumption can cause unexpected health problems in a subset of individuals with pre-existing thyroid disorders. Although it is reported that excessive iodine does not cause thyroid antibody positivity, high intake can cause or worsen symptoms for people with previous thyroid autoimmunity or other underlying thyroid issues [ 47 ]. Transient hypothyroidism and iodine-induced goiter is common in Japan and can be reversed in most cases by restricting seaweed intake [ 16 , 29 , 48 – 52 ]. In Asian cultures, seaweed is commonly cooked with foods containing goitrogens such as broccoli, cabbage, bok choi and soy [ 18 ]. The phytochemicals in these foods can competitively inhibit iodine uptake by the thyroid gland (i.e., isothiocyanates from cruciferous vegetables) [ 53 – 55 ], or inhibit incorporation of iodine into thyroid hormone (i.e., soy isoflavones) [ 56 , 57 ]. Certain species of seaweed can concentrate bromine, a halide similar to iodine with no known physiological function, at very high levels [ 58 , 59 ]. If seaweeds with elevated levels of bromine and low levels of iodine are consumed when the body is in an iodine deficient state, inhibition of thyroid hormone synthesis--due to bromine's attachment to tyrosine residues on thyroglobulin in place of iodine--is plausible [ 60 ]. Estimate of daily iodine intake in Japan We estimate that the average Japanese iodine intake, largely from seaweed consumption--based on dietary records, food surveys, urine iodine analysis and seaweed iodine content--is 1,000-3,000 μg/day (1-3 mg/day). This estimate compares to a recent report claiming that the average iodine intake of the Japanese from kelp is around 1,200 μg/day (1.2 mg/day) [ 19 ]. Iodine intake can vary from day-to-day depending on diet, and it is unlikely for a single persons iodine intake to remain constant for an extended period of time. With the multitude of edible seaweeds (each with different iodine content) consumed in the Japanese diet, it is not appropriate to use a single type of seaweed to determine iodine intake, though many estimates do. Although seaweed provides a majority of the Japanese iodine intake, other food sources (containing far less iodine)--such as fish and shellfish--can increase the total amount of iodine consumed daily. Conclusions Japanese iodine intake from seaweed is linked to health benefits not seen in cultures with dissimilar diets. 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Written by Adam Gesing , Andrzej Lewiński  & Małgorzata Karbownik-Lewińska   Thyroid Research volume 5 , Article number: 16 (2012)                                                                                     Abstract The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known. It is to be stressed that the clinical course of thyroid diseases in the elderly differs essentially from that observed in younger individuals, because symptoms are more subtle and are often attributed to normal aging. Subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, require special attention in elderly subjects. Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels – progressively shifting to higher values with age – may contribute to the increased lifespan. This short review focuses on recent findings concerning the alterations in thyroid function during aging, including these which may potentially lead to extended longevity, both in humans and animals. Introduction The endocrine system and particular endocrine organs, including the thyroid gland, undergo – similarly to other organ systems – crucial functional changes with aging. Numerous morphological and physiological changes of the thyroid during the process of aging are well-known [ 1 – 3 ]. A specificity of thyroid diseases in the elderly, differing essentially from that observed in younger subjects, relies on the presence of more subtle symptoms which are often attributed to normal aging. Therefore, subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, the prevalence of which increases with age, require special attention in elderly subjects. Interestingly, altered thyroid function may contribute to the extended longevity. The present review focuses on the newest findings concerning the alterations in thyroid function during the process of aging. Thyroid dysfunction with aging The process of aging affects both the prevalence and clinical presentation of hypo- and hyperthyroidism. Importantly, subclinical disturbances of thyroid function are more frequent than overt diseases in general population, as well as in elderly people [ 4 , 5 ]. Consistently, the prevalence of subclinical hypothyroidism, which is characterized by normal free thyroxine (FT4) and elevated thyrotropin (TSH) levels, increases with aging [ 6 – 12 ] and ranges from 3 to 16% in individuals aged 60 years and older [ 13 ]. Although it is known that overt thyroid disorders negatively affect physical and cognitive function in elderly people – for example, overt hypothyroidism is associated with the impairment of attention, concentration, memory, perceptual functions, language, and executive functions [ 14 ], subclinical hypothyroidism is not associated with impairment of physical and cognitive function or depression in individuals aged 65 years and older, as compared to euthyroidism [ 15 ]. Also Park et al. [ 16 ] have demonstrated that subclinical hypothyroidism in elderly subjects is neither associated with cognitive impairment, depression, poor quality of life nor with metabolic disturbances. On the other hand, other studies demonstrated the presence of – at least – mild cognitive impairment in people with subclinical hypothyroidism at mean age under 65 years (reviewed in [ 17 ]). Furthermore, as reported by de Jongh et al. [ 15 ], subclinical hypothyroidism was also not associated with the increased overall mortality risk. Similar findings were shown by Rodondi et al. [ 18 ] who analyzed data from numerous large prospective cohorts and demonstrated that total mortality was not increased in subjects with subclinical hypothyroidism, although the risk of coronary heart disease (CHD) events and of CHD mortality increased with TSH levels 10 mIU/l or higher. Nevertheless, it should be emphasized that this analysis regarded numerous different populations (cohorts) which consisted of not only elderly people and that the effect in question, i.e. of increasing TSH level on CHD incidents was not influenced by age [ 18 ]. Undoubtedly, there are obvious indications for treatment of overt hypothyroidism. On the other hand, indications for treatment of subclinical hypothyroidism are still controversial. Despite improvement of lipid profile due to treatment of subclinical hypothyroidism, there is no clear evidence that this beneficial effect can be associated with decreased cardiovascular or all-cause mortality in elderly patients [ 19 ]. Furthermore, Parle et al. [ 20 ] have reported that L-thyroxine replacement therapy does not improve cognitive function in elderly individuals with subclinical hypothyroidism. When the natural history of subclinical hypothyroidism was evaluated in the elderly, the final results depended on the presence or absence of thyroid antibodies and on that to what extent TSH concentration was increased. Thus, a quite high rate of reversion of subclinical hypothyroidism to euthyroid status in adults aged at least 65 years with lower baseline TSH levels and antithyroid peroxidase antibody (TPOAb) negativity was observed [ 21 ]. In turn, higher TSH level and TPOAb positivity were independently associated with lower chance of reversion to euthyroidism [ 21 ]. Moreover, TSH levels ≥ 10 mIU/l were independently associated with progression to overt hypothyroidism [ 21 ]. Similar findings, showing that higher baseline TSH levels are associated with progression from subclinical to overt hypothyroidism and that higher TSH level (> 8 mIU/l) is a predictive value for development of overt hypothyroidism, were recently reported by Imaizumi et al. [ 22 ]. On the other hand, there is strong evidence that thyroid hypofunction may contribute to increased lifespan (see further in the text). Therefore, taking into account all mentioned observations, the replacement therapy with L-thyroxine is not uniformly recommended in elderly people with subclinical hypothyroidism. In turn, subclinical hyperthyroidism, characterized by serum TSH levels below lower limit of the reference range and normal serum FT4 levels, is observed in about 8% of individuals aged 65 years and older [ 23 ]. Subclinical hyperthyroidism may be associated in older adults with decreased bone mineral density and fractures [ 24 ], or cognitive impairment [ 23 ] (reviewed in [ 25 ]). Furthermore, subclinical hyperthyroidism is associated with increased risk of total, as well as CHD mortality and atrial fibrillation (AF) incidents [ 26 ]. The highest risks of CHD mortality and AF are observed in the case of TSH levels lower than 0.1 mIU/l [ 26 ]. Unexpectedly, de Jongh et al. [ 15 ] have reported that subclinical hyperthyroidism is not associated with impairment of physical and cognitive function or depression in elderly people, aged 65 years and older. These authors have also demonstrated that subclinical hyperthyroidism is not associated with the increased overall mortality risk [ 15 ]. Such results are quite difficult to explain. Presumably, that ambiguity in observations may result from differences in the number of individuals enrolled in particular studies or from follow-up duration. Interestingly, Rosario [ 27 ] has recently shown that progression of subclinical hyperthyroidism to overt hyperthyroidism in elderly patients is an uncommon observation. Nevertheless, since subclinical hyperthyroidism (and obviously, overt hyperthyroidism with increased T4 level) may lead to increased risk of total, as well as CHD mortality, patients older than 65 years, with low TSH levels – particularly in case of toxic multinodular goitre or a solitary autonomous thyroid nodule – require proper medical treatment (e.g. [ 11 ]). It should also be stressed that during aging, gender-specific alterations in TSH and free thyroid hormone levels were observed [ 28 ]. Namely, with increasing age in males there were decreases in free thyroid hormones but not in TSH concentrations. In turn, in females, the free thyroid hormone levels were not changed with aging but TSH level increased in age-dependent manner [ 28 ]. Most recent results indicate that even in euthyroid older men with normal levels of TSH, differences in FT4 levels within the normal range predict specific health outcomes relevant to aging. For example, higher FT4 within the normal range was independently associated with frailty in euthyroid men aged ≥70 years [ 12 ]. Moreover, higher FT4 levels within the normal range were associated with lower hip bone mineral density, increasing bone loss and fracture risk in postmenopausal women [ 29 ]. Therefore, it seems that further studies are required to explain whether higher FT4 levels contribute causally (or not) to the above mentioned poorer health outcomes. Moreover, it is of interest to clarify whether FT4 levels in the low-normal range could be considered as potential biomarkers for healthy aging [ 12 ]. Although numerous studies demonstrate that the increased TSH level resulting from subclinical hypothyroidism further rises with aging [ 6 – 12 ], other findings suggest that aging is associated – in the absence of any thyroid disease – with lower TSH levels [ 30 – 35 ]. It has been known that TSH secretion in response to thyrotropin-releasing hormone (TRH) is reduced in aging individuals, and serum TSH level is usually lower in older than in young people in response to decreased thyroid hormone concentrations, suggesting a certain level of insensitivity of thyrotrophic cells in anterior pituitary, occurring with age; moreover, nocturnal surge of TSH is – to various degree – lost in the elderly (reviewed in [ 1 ]). On the other hand, Bremner et al. [ 10 ] have recently reported that the TSH increase – observed by other authors during aging – seems to be a consequence of age-related alteration in the TSH set point or reduced TSH bioactivity. Interestingly, the largest TSH increase is observed in people with the lowest TSH at baseline, and, in turn, people with higher baseline TSH levels had proportionally smaller increases in TSH concentrations [ 10 ]. It is worth adding that TRH and FT4 serum levels do not differ between young, middle-aged and elderly subjects [ 34 ]. Thyroid dysfunction and longevity As it has been mentioned above, the alterations in levels of hormones related to pituitary-thyroid axis are associated with the process of aging and, thus, may impact longevity. However, a direction of these changes, which may lead to increased lifespan, still seems to be not fully determined [ 6 – 12 , 30 – 35 ]. One should emphasize that the most striking findings concerning potential contribution of TSH and thyroid hormones to lifespan regulation, were obtained in the studies performed on centenarians (and almost centenarians). In 2009, Atzmon et al. [ 7 ] published the results of studies on thyroid disease-free population of Ashkenazi Jews, characterized by exceptional longevity (centenarians). They have observed higher serum TSH level in these subjects as compared to the control group consisted of younger unrelated Ashkenazi Jews, as well as to another control group obtained from The National Health and Nutrition Examination Survey (NHANES) program of studies [ 7 ]. Therefore, these findings appear to support previous observations, indicating that serum TSH shifts progressively to higher levels with age (e.g., [ 36 ]). Moreover, the authors have observed an inverse correlation between FT4 and TSH levels in centenarians and Ashkenazi controls, and finally, they have distinctly concluded that increased serum TSH is associated with extreme longevity [ 7 ]. In another study, a role of genetic background, potentially responsible for the above-mentioned changes, was assessed [ 37 ]. It turned out that two (2) single nucleotide polymorphisms (SNPs) in TSH receptor (TSHR) gene, namely rs10149689 and rs12050077, were associated with increased TSH level in the Ashkenazi Jewish centenarians and their offspring [ 37 ]. The above-mentioned inverse correlation between FT4 and TSH in centenarians may suggest a potential role of decreased thyroid function in lifespan regulation, leading to remarkable longevity. Such a hypothesis seems to have been confirmed by the findings obtained in the Leiden Longevity Study, demonstrating the associations between low thyroid activity and exceptional familial longevity [ 38 ]. In turn, Corsonello et al. [ 39 ] have demonstrated that age is associated with a decrease in free triiodothyronine (FT3) and FT4 but not with increased TSH levels. Moreover, children and nieces/nephews of centenarians had lower FT3, FT4 and TSH levels as compared to the age-matched subjects [ 39 ]. It may, at least partially, confirm an important role of low thyroid function in the regulation of lifespan. It should be stressed that reduced thyroid function with low levels of T4 is associated with extended longevity also in animals [ 40 – 42 ]. For example, a very severe thyroid hypofunction with reduced core body temperature, as observed in Ames dwarf (df/df) and Snell mice (characterized by mutations at the Prop-1 and Pit-1 gene, respectively, and demonstrating a lack of growth hormone (GH), prolactin and TSH), is considered to substantially contribute to remarkable longevity in these rodents [ 40 ]. Furthermore, severe hypothyroid Ames dwarfs and mice with targeted disruption of the growth hormone receptor/growth hormone binding protein gene (GH receptor knockout; GHRKO) with mild thyroid hypofunction, have decreased thyroid follicle size which may explain decreased thyroid hormone levels in these mutants [ 43 ]. Concluding, the findings in animals are consistent with the results obtained in humans and may confirm a relevant role of thyroid hypofunction in lifespan extension. Thyroid cancerogenesis and aging processes The prevalence of thyroid nodules and thyroid neoplasms is increased in the elderly. Among elderly people, males are at higher risk of cancer and thyroid cancer is more aggressive in men than in women [ 44 ]. Papillary thyroid carcinoma (PTC) is the most common endocrine malignant neoplasm in the older individuals. Women are affected by PTC two to three times more often than men [ 45 ]. Nevertheless, female-to-male ratio seems to decline with the process of aging [ 45 ]. Importantly, the mortality rate of PTC is usually higher in the elderly [ 46 ]. Presumably, it is a consequence of increased mitotic activity of these tumors and increased likelihood of distant metastases [ 46 ]. It is known that in general population patients with aggressive variants of PTC have higher risk for the metastatic disease development [ 47 ]. The potential role of NDRG2 gene expression in the development and progression of PTC is also raised [ 48 ]. It is worth recalling that mutated BRAF gene is an independent predicting factor of poor outcome in PTC and is related to advanced age [ 49 ]. Follicular thyroid carcinoma (FTC) occurs also often in older people and is the second most common and the second least aggressive thyroid cancer. This cancer is more likely to metastasize hematogenously to distant sites, resulting in a worse prognosis in comparison with PTC [ 44 ]. Medullary thyroid carcinoma (MTC), which derives from the parafollicular cells (C cells) of the thyroid gland, constitutes up to 5% of all thyroid malignancies. Its sporadic form, more frequent than is familial MTC, occurs more commonly in the older population [ 50 ]. Rapidly growing and typically very aggressive anaplastic (undifferentiated) thyroid carcinoma (ATC) is rare. However, one should strongly emphasize that its prevalence is considerably higher in older than in younger people. By the time of diagnosis, most patients have widespread local invasion and distant metastases. Age appears to be a strong predictor of poor prognosis in ATC [ 44 ]. Conclusions The process of aging strongly affects entire endocrine system. Consistently, thyroid gland is also impacted by aging. One should emphasize that thyroid diseases-associated symptoms in the elderly people are very similar to symptoms of the normal aging. Therefore, broadening the knowledge on alterations in thyroid function, which may be observed during aging, appears to be very important and constitutes a challenge for thyroid researchers, given that some specific thyroid dysfunctions may contribute to lifespan extension. 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Written by Tim I. M. Korevaar   Thyroid Research volume 11 , Article number: 5 (2018) Abstract Physiological changes necessitate the use of pregnancy-specific reference ranges for TSH and FT4 to diagnose thyroid dysfunction during pregnancy. Although many centers use fixed upper limits for TSH of 2.5 or 3.0 mU/L, this comment describeds new data which indicate that such cut-offs are too low and may lead to overdiagnosis or even overtreatment. The new guidelines of the American Thyroid Association have considerably changed recommendations regarding thyroid function reference ranges in pregnancy accordingly. Also a stepwise approach to interpreting these guidelines is discussed as well as the relevant role of FT4 in diagnosis. Background Thyroid physiology changes during pregnancy and this necessitates the use of pregnancy-specific reference ranges for TSH and FT4 in order to adequately diagnose gestational thyroid disease [ 1 ]. Currently, many centers use a reference range for TSH with an upper limit of 2.5 mU/l in the first trimester and 3.0 mU/l in the second or third trimester to diagnose subclinical and overt hypothyroidism. This is based on outdated international guidelines from the American Thyroid Association (2011), the Endocrine Society (2012) and the European Thyroid Association (2014) [ 2 , 3 , 4 ]. Although each of these guidelines recommend to calculate lab-specific reference ranges for TSH and FT4, many centers do not have such reference ranges available. Instead, most centers adhere to the former second recommendation which is that, in the absence of lab-specific reference ranges, fixed upper limits for TSH (2.5 mU/l in the first and 3.0 mU/l in the second and third trimester) can be used. However, recent studies have indicated that these cut-offs are too low and may lead to overdiagnosis and unnecessary treatment, or even overtreatment. Based on some important findings discussed below, the 2017 American Thyroid Association guidelines have updated the recommendations on the upper limit for TSH during pregnancy. Main text Various studies have demonstrated that with the use of fixed TSH upper limits, 8–28% of pregnant women have a TSH concentration that is considered too high [ 5 , 6 ]. These numbers are much larger than the roughly 3–4% that would have a too high TSH if population-based reference ranges would be used to define the upper limits for TSH. Medicalization of a group of women as large as 8–28% is unwarranted, unsustainable and likely to cause more harm than benefit. Further data indicate that the upper limit for TSH should be higher. By summarizing 14 studies that calculated population-based pregnancy-specific reference ranges for TSH and/or FT4, our group was able to show that in more than 90% of all studies, the upper limit for TSH was above 2.5 or 3.0 mU/l [ 7 ]. Moreover, the few studies performed in a population that was proven to be iodine sufficient report an upper limit for TSH of 4.04 and 4.34 mU/l [ 7 ], however, the effects of population iodine status on reference range values remains to be studied. Interestingly, a large randomized controlled trial that screened approximately 100.00 pregnant women for subclinical hypothyroidism and hypothyroxinemia using the fixed TSH cut-offs [ 8 ] had to amend its protocols because the TSH upper limit turned out to be 4.0 mU/l after roughly 15.000 women were screened. The 2017 ATA guidelines [ 9 ] now recommend the following: Calculate pregnancy-specific and lab-specific references ranges for TSH and FT4 If 1 is not possible, adopt a reference range from the literature that is derived using a similar assay and preferably also in a population with similar characteristics (i.e. ethnicity, BMI, iodine status) If 1 and 2 are not possible, deduct 0.5 mU/l from the non-pregnancy reference range (which in most centers would results in a cut-off of roughly 4.0 mU/l) My interpretation of these recommendations is probably more strict than that of most endocrinologists or gynecologists. Lab-specific reference ranges better identify women with gestational thyroid dysfunction than reference ranges defined by another methodology [ 7 , 10 ]. Calculating lab-specific references ranges is not difficult and every hospital in which prenatal care is provided would be able to perform a good study at very low costs (i.e. less than a few thousand euro/GBP), particularly when collaborating with the clinical chemistry department. Adequate reference ranges can be obtained by selecting at least 400 pregnant women with a singleton pregnancy, free of pre-existing thyroid disease, that do not use thyroid interfering medication, that did not undergo IVF treatment and are TPOAb negative [ 7 ]. Therefore, I believe that if a center does not have lab-specific reference ranges readily available, physicians should not automatically move to step 2 or 3 of the guideline recommendations, but try to obtain lab-specific reference ranges. Calculating such reference ranges will instantly improve the quality of clinically diagnosing thyroid dysfunction in pregnancy. When specific expertise is missing, groups involved in the field of thyroid and pregnancy (including our group) would be more than willing to share their experience. Although it seems clear that fixed upper TSH limits of 2.5 mU/l or 3.0 mU/l can no longer be considered adequate, the new ATA guidelines seem to make one exception. A new recommendation indicates that levothyroxine treatment can be considered for a TSH above the reference range in TPOAb negative women, while for TPOAb positive women treatment can be considered from a TSH above 2.5 mU/L [ 9 ]. This is based on data from observational studies showing that there is a higher risk of miscarriage and premature delivery in TPOAb positive women with high-normal TSH concentrations (i.e. above roughly 2.5 mU/L). However, new studies published only shortly after release of the new guidelines could not show any beneficial effect of levothyroxine treatment for women with a TSH above 2.5 mU/L, but did find beneficial effects for women with a TSH above 4.0 mU/L [ 11 , 12 , 13 ]. However, larger studies are needed to confirm these findings and identify the true TSH concentration from which the outcome of clinical adverse outcomes is increased. While much focus has gone into defining the upper limit for TSH, the definition of thyroid dysfunction is also dependent on the FT4 concentration. For example, in a hypothetical patient with a TSH of 5.5 mU/l, the FT4 concentration will decide whether there is overt hypothyroidism or subclinical hypothyroidism. The distinction between these clinical disease entities can have major consequences for the clinical work-up and approach. Although some studies have casted doubt about the validity of FT4 immunoassays during pregnancy, it is important to realize that the vast majority of patients present during early pregnancy during which the assay interference by thyroid hormone binding proteins is not relevant (only relevant during the third trimester). Moreover, lab-specific reference ranges for FT4 will still correctly identify women with true low or true high FT4 given that there is a high correlation between FT4 concentrations measured by immunoassays and after disequilibrium dialysis or with LCMS [ 1 ]. The alternative of increasing the non-pregnancy limits for total T4 by 150% does not seem viable given the gestational age specific changes and lack of association of total T4 with adverse outcomes [ 1 , 14 ]. Conclusions In conclusion, any hospital or physician that is still using the 2.5 or 3.0 mU/l cut-off for TSH during pregnancy should re-evaluate their practice. 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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.

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.