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John Midgley B Sc (Leeds), D Phil (Oxford) has written this summative article exclusively for Thyroid UK. There have been long, sad and unsatisfactory developments in the history of thyroid testing, including up to the present day. The first thyroid function test, in the form such tests are used today, appeared in 1960. This measured total thyroxine (T4). Before this, a convenient measurement of thyroid hormones was not possible. 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. Thyroid testing goes commercial In about 1975, commercial TSH and T3 tests were developed and sold. 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). Such was the growing demand for thyroid testing that the various companies competed with one another for business in the labs. Since the method of measurement (radioactivity) was the same in all tests, the competition was such that no company would have a monopoly of business in the labs. This competition produced faster and slicker tests with shorter and shorter times – giving quicker turnover and more tests done in a given time. 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. The London researcher (now a distinguished professor – Nobel Laureate just failed), who had developed the pioneering total test 20 years earlier invented a validly based test for FT4. At the same time, I invented and my company developed and offered a method based on a different principle, but also soundly based. My method as initially developed was not perfect – there were obscure areas of thyroidology where there were problems but we’d identified them and given the advice to circumvent. The professor’s method was sound but suffered from the fact that there were several steps to take before you got an answer, which took time and cost precision – the more handling, the more progressive errors creep in. On the other hand, the thyroid testing I had invented was, in the hands of the lab technician exactly the same in handling as the existing total T4 test – a big time/turnover/precision advantage for the busy lab. The London professor and his group decided to try to destroy the validity and reputation of the rival test and those who had developed it. So began a long series of aggressive, long and detailed theoretical arguments as to why the test I had invented was, in its present form, unfit for purpose and could not and did not work. In vain did we show that the practical working of our test bore no resemblance whatever to his theoretical predictions – this only invited more and more vituperative denunciation. This aggressive, acrimonious and almost libellous controversy (the worst in the history of any discipline in clinical chemistry) continued for almost 20 years before dying out in the futility with which it had started. During this time, the average clinical chemistry worker in the average hospital was totally oblivious to all this rarefied argument and was happy that at last, a reliable FT4/FT3 test was available. For example, it brought into the diagnostic fold even the most TBG-extreme people mentioned earlier. For a while, there was a golden age in thyroid diagnosis where all tests (TSH, FT4, FT3 were used – especially in Germany and Japan). In the mid-eighties, 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%. I 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. In 1988 I and my 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. Shortly after, I left the field of thyroid testing entirely for 10 years, only returning by accident in 1999. Thyroid testing in chaos On returning to the field I found it in chaos. 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. I 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. 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 I 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 – scientific honesty? Thyroid testing’s triple failure Now we come to the present day. We have simultaneously in existence licensed, manufactured and used in diagnosis, thyroid testing based on the discredited thyroid hormone uptake test, tests based on sound methodology but including the earlier imperfect tests up to the modern improved ones, and tests offered that are to be run invalidly at room temperature. This implies a complete failure to regulate by the international regulators whose job it is to ensure the equivalence of results. The composite failure of the manufacturers to produce consistent FT4 and FT3 tests has already been mentioned. The failure of the medical thyroidology fraternity to ensure consistency of the tests they use is an additional factor in the diagnostic chaos that is now present. No wonder TSH only screening has gained credence in such an atmosphere. There is a triple failure that has led to a diagnostic hiatus that urgently needs correcting. The paradigm of the TSH-FT4 relationship is wrong, especially in treatment. The whole conceptual thinking behind diagnosis thyroidology and the importance of personal diagnosis based on the patient rather than whether the numbers fall in or out of the normal range is fatally flawed. For the moment mechanical thinking has traduced medical diagnosis.

Written by Gaute Tyssebotn 13.11.04 Updated 23.01.06 Originalspråk: Norwegian Many people see having children as a given, but more and more women are experiencing problems getting pregnant. The diet can be the problem. One of the most important reasons for involuntary childlessness among women is polycystic ovary syndrome (PCOS), but in many cases it can be improved with the help of diet. As obesity becomes increasingly common in the population, the number of women who cannot have children also increases. This is no coincidence as obesity can often be a symptom of an imbalance in the body's hormones. Insulin is central, and in many ways can be seen as the "boss" among the hormones. Avoid being overweight Too much of this hormone can also help create disturbances in other hormone systems, including stress hormones, metabolic hormones and growth hormone, and in the reproduction hormones. A diet rich in carbohydrates, such as bread, pasta, rice, cereal products in general, potatoes, sugar, ready-made products and the likes, will cause a greater rise in blood sugar and, in turn, more secretion of insulin. Eventually, you can develop what we call insulin resistance, a condition where large amounts of insulin are produced, but the insulin no longer works well enough. Since insulin is responsible for storing fat in the fat depots, a carbohydrate-rich diet can lead to obesity, which can further worsen insulin resistance. Perhaps the most common reason for involuntary childlessness in women in the Western world is PCOS, and this syndrome is strongly linked to precisely insulin resistance. Although insulin resistance is most common in obese people, there are also many exceptions. The most effective way to improve insulin resistance is diet, and therefore it is no coincidence that many women have experienced becoming pregnant after changing to less carbohydrates and more fat. Poly cystic ovary syndrome – PCOS It is important to distinguish between PCO and PCOS, as they are two different things. PCO, or polycystic ovaries, is characterized by growths or cysts on the fallopian tubes, and nothing else. These cysts can either sit together or be spread over the entire fallopian tube. A few cysts that come and go are not uncommon in many women of childbearing age, but only when there are eight or more cysts in a cross-sectional view on an ultrasound scan or 12 or more in total on the entire fallopian tube is the condition called PCO. PCO is much more common than PCOS and initially no problem, although you should always have a doctor examine the cysts regularly. If you have reached menopause or past it, and you still have such cysts, it is important to be vigilant. The cysts can become malignant and cause cancer, and therefore your doctor will probably choose to remove any cysts at this time. Why you get PCO is unclear, but it is believed that genetic factors play a role, among other things. It is claimed that 20-25 percent of all women of childbearing age have PCO. PCOS, or Poly cystic ovary syndrome, is a spectrum of various ailments or symptoms and not only linked to cysts on the fallopian tube. Usually, PCOS will always be found in PCOS, but some doctors give the diagnosis of PCOS without the presence of cysts on the fallopian tubes. With PCOS, it is very common to have higher production of the male sex hormone testosterone and insulin resistance. This can cause many disturbances, and the three most common indications of PCOS are obesity (applies to up to 80 per cent), unwanted/larger hair growth (applies to up to 90 per cent) and irregular menstruation (applies to up to 90 per cent). Other typical problems are acne, hair loss, bleeding and reduced fertility, but it can also be more or less common with concentration difficulties, high blood sugar, enlarged ovaries, increased risk of miscarriage, depression, migraines, metabolic problems, PMS symptoms, swollen hands, feet and face, problems with the stomach (slow or loose stomach), low heart rate, fatigue and impaired memory. As many as 10 percent of women of childbearing age may have PCOS, making up a significant proportion of those struggling to conceive. Diagnosis of PCOS Finding out if you have PCOS can be done in several steps. Your doctor will want to get a detailed medical history about your menstrual cycle, contraceptive use and any pregnancies. The doctor will also carry out an abdominal examination to find out if you have cysts on swollen/enlarged fallopian tubes. If cysts are found, it is common to carry out an ultrasound examination, but also to take blood tests to check the hormone status in the body. Women with PCOS may have elevated levels of testosterone and insulin. Besides checking the levels of these two hormones, it is also a good idea to check SHBG (sex hormone binding globulin). The sex hormones are fat-soluble and use to bind to special accompanying proteins, called hormone binders. SHBG has an easier time binding to testosterone than estrogen. Estrogen increases the production of SHBG, which is also the reason why women normally have more SHBG in their blood than men. Low levels of SHBG in a woman indicate that there is more free testosterone than usual. Triglyceride and cholesterol levels are also checked occasionally, as they are often abnormal in PCOS. Early indications of PCOS can already be seen at the age of 12-13 when puberty begins. Many doctors believe that girls who have not menstruated before the age of 16 should be examined for PCOS. It is also not unusual for menstruation to be normal at the start, but as the girls approach their 20s it becomes more and more unstable. The use of birth control pills can cause a "false" menstrual cycle, since these drugs increase the amount of estrogen and thus balance out the increased amounts of testosterone. When they stop taking birth control pills to get pregnant, the period does not return or is very irregular. What causes PCOS? Things may indicate that genetics play a role in this syndrome, but there are also clearly lifestyle factors involved, as PCOS has become more common in recent decades. Studies show clear connections between insulin resistance and greater production of male sex hormones. Usual medical treatment For women who do not want to become pregnant, it is common to use birth control pills to control the many and problematic symptoms. Use of cyclic progestagen, a progesterone-like hormone, but also progesterone is occasionally given for PCOS. Women who want children are often given injections and other drugs to improve the development of egg cells. The treatment requires accuracy and is usually carried out by experienced doctors in the field. Some of the medicines increase the chance of overstimulation, so that the chance of becoming pregnant with more children increases. Insemination and test tube treatment are also not uncommon. Type 2 diabetes is characterized by insulin resistance, and since insulin resistance is also common in PCOS, it is not surprising that up to 40 percent of those with PCOS develop type 2 diabetes. Medicines for type 2 diabetes, metformin and glucophage, which aim to lower insulin secretion by improving insulin sensitivity, has also been shown to be helpful for PCOS patients who want to get pregnant. As well as lowering insulin secretion, it is believed that these medicines also enhance the effect of other medicines, which stimulate ovulation. Get pregnant with the right diet? There is no complete cure for PCOS, but like type 2 diabetes, it can be controlled. Leading experts believe that diet is the most important thing in the treatment of PCOS. With the help of the diet, one can easily get the body to produce less insulin, thereby improving a probable insulin resistance. The higher the rise in blood sugar after a meal, the greater the insulin secretion, and the greater the obesity can become. Since it is mainly the amount and type of carbohydrates that affect blood sugar and insulin secretion, it is of great importance in PCOS to reduce the amount of carbohydrates in the diet. Carbohydrates are found in abundance in bread, pasta, rice, cereal products in general, potatoes, sugar, many ready-made products, juices, sweet drinks, jams, etc. It is advantageous to replace many of these foods with other foods rich in natural fat, such as eggs, bacon, meat, fatty fish (but also other types of fish), fatty dairy products, coconut fat, olive oil, etc. Fat has the great advantage that it does not affect the secretion of insulin to any significant extent, it stabilizes blood sugar and it has a very positive effect on feelings of hunger and satiety. Less insulin secretion will most likely result in weight loss, and studies and experience have shown that just a few kilos of weight reduction will make it easier for women with PCOS to get pregnant. Since low-carbohydrate diets have a particularly good effect on reducing weight, they have also been shown to be very useful in infertile women with PCOS. The essential fatty acid omega 3 can prove effective in PCOS, since among other things it will be able to lower the need for insulin. Since there are few foods that contain larger amounts of this fatty acid, it is often wise to take supplements in the form of capsules, cod liver oil, Udo's Choice or Vega Max. Other supplements that can be good are chromium, which helps insulin to do a better job. Improving the calcium balance, through supplements of calcium, magnesium and vitamin D3, has been shown in studies to improve the chances of women with PCOS having children. Finally, it is always recommended to take a multivitamin and mineral product rich in antioxidants. References: Thatcher SS. PCOS – The hidden epidemic. Indianapolis: Perspectives Press, 2000.Murray RK, Granner DK, Mayes PA, Rodwell VW. Harper’s Biochemistry – 25th edition.New York: Appleton & Lange, 2000Harris C. PCOS dietbook. London: HarperCollinsPublisher Limited, 2002Thys-Jacobs S et al. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Elsevier Science 1999; 64: 430-435

Broda Otto Barnes (April 14, 1906 - November 1, 1988) was an American physician who became an authority in the diagnosis and treatment of hypothyroidism. He spent more than 50 years of his life researching and treating endocrine dysfunctions, specializing in the thyroid gland. Barnes is credited for several important discoveries in the field of endocrinology pertaining to the thyroid gland. These include: * developing a simple diagnostic test for hypothyroidism: "Barnes Basal Temperature Test". * realizing the inadequacy of thyroid diagnostic tests * discovering that the prevalence of undiagnosed hypothyroidism has risen to over 40% of the American population. * realizing the superiority of desiccated thyroid extract over synthetic drugs, in treating hypothyroidism. * showing hypothyroidism is a cause of other chronic diseases including heart disease. Barnes' views were never widely adopted in mainstream medicine, yet they continue to be vigorously supported by some practitioners. Barnes was born on April 14, 1906, in a log cabin in Missouri, the son of Addie and Robert B. Barnes. Barnes studied chemistry at the University of Denver, and became an instructor of physiological chemistry at Western Reserve University for two years, receiving his M.S. in 1930. Barnes received his Ph.D. from the University of Chicago in 1931 and taught physiology there from 1931 to 1936. He completed his M.D. in 1937 at Rush Medical College, and for two years he was an assistant professor of medicine at the University of Illinois. He was named chairman of the Health Education Department at the University of Denver. He became professor affiliate in the department of physiology at Colorado State University from 1963 to 1968. On 13 September 1981 he married Helen Tucker Morgan (1905–2002) in California. She was his second wife. In 1984, Barnes established a not-for-profit foundation, the Broda O. Barnes Research Foundation, to continue to advocate his arguments about hypothyroidism. Barnes and his wife also established a program of interest-free student loans to aid "worthy and needy chemistry students" at the University of Denver. The University of Chicago library retains a collection of memorabilia, consisting largely of photographs related to Barnes' time there. He died 1. November 1988 in Bend, Oregon. Diagnosis of Hypothyroidism Perhaps Barnes' most celebrated accomplishment was the invention of a diagnostic test for thyroid function, now known as the "Barnes Basal Temperature Test". This test is performed by placing a thermometer in the armpit for 10 minutes immediately upon waking. A measurement of 97.8F (36.6C) or below was considered by him to be highly indicative of hypothyroidism, especially when hypothyroid symptoms are present. A reading over 98.2F (36.8C) was indicative of hyperthyroidism. (Menstruating women must take this test on day 2-4 their cycle; When using a digital thermometer, the button must be pressed at the 10 minute mark). The details of the test were published in the Journal of the American Medical Association (JAMA) in August of 1942 ("Basal Temperature vs. Basal Metabolism"), and again in The Lancet in 1945. Though the test was not widely adopted by the medical professional as a whole, it was and continues to be enthusiastically endorsed by a minority of medical doctors and many alternative practitioners. Barnes didn't consider his Basal Temperature Test to be 100% conclusive, and acknowledged there were other causes of lowered basal temperature. Nevertheless, he maintained that it was the most useful diagnostic test in the diagnosis of hypothyroidism, superior even to all modern bloodtests. Barnes considered modern bloodtests--like the Basal Metabolism Test and the Protein BoundIodine Test to be unreliable, leaving many patients with clinical symptoms of hypothyroidism undiagnosed and untreated. Barnes estimated in the 1980's, that the prevalence of undiagnosed hypothyroidism had risen to affect more than 40% of the American population. Treatment of Hypothyroidism Barnes treated hypothyroidism by prescribing patients a daily dose of thyroid hormone. He recommended starting with a small dose (1 grain for a healthy adult, 1/4 grain for children), then slowly increasing the dosage in monthly intervals until symptoms resolved. For most patients, he recommended continuing thyroid medication for life at that optimal dose, though some could be slowly weened off. He advised patients to take the thyroid medication first thing in the morning on an empty stomach, at least 20 minutes before food. Barnes used desiccated thyroid extract almost exclusively, noting that patients experienced much better improvement of symptoms with the natural extract, rather than synthetic drugs. He claimed that even with synthetic combination drugs containing T4 and T3, patients were left with symptoms (dry skin & fluid retention), that upon switching to desiccated thyroid extract would resolve. This observation lead Barnes to speculate that there are additional undiscovered active components in the natural extract besides T4 and T3. Modern research has revealed that T2 (diidothyronine) and T1 (monoidothyronine) are also present, though their function is still not fully understood. During his years of practice, Barnes also began to conclude that virtually all his hypothyroid patients had a concomitant adrenalin insufficiency. Following this discovery, he routinely gave an accompanying physiological dose of adrenal steroid (Prednisone 5mg/day) together with desiccated thyroid extract. Barnes found this especially mandatory in patients showing more severe adrenal insufficiency exhibited by low systolic blood pressure (below 100). Heart Disease Barnes performed significant research into the cause of heart disease. During his lifetime he spent many summers in Graz, Austria, reviewing and researching autopsy reports in the city hospital. The Graz autopsy records are widely considered to be the oldest and most complete in the world, and came as a result of the decree of empress Maria Theresa of Austria over 200 years ago, that autopsies are mandatory for all hospital deaths in the city of Graz. His 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. The cholesterol theory of heart disease credits the drop in consumption of fatty foods during the war years for the drop in heart attacks, and the increase of heart attacks after the wars end with the resumed availability of fatty foods. Barnes’ autopsy research however, showed that in the war years when the rate of deaths from heart attacks dropped, the patients who were dying—largely due to Tuberculosis--had greatly accelerated rates of atherosclerosis. Barnes pointed out that the vast majority of patents who had died would have died from a heart attack soon after if the infection had not killed them first, and furthermore that the patients were largely hypothyroid. Barnes concluded then, that the hypothyroid patient is both susceptible to infection and atherosclerosis, and it is a question of circumstances that will determine which will be fatal first. Thus the drop and rebound of heart attacks during the and after the war years can be attributed to an increased rate of infectious disease during the war, and a sharp decrease after the war due to the availability of antibiotics. Barnes also conducted a multi-decade study of his own patients, that showed a 94% reduction in the rate of heart attacks as compared to the Framingham Heart Study. Barnes concluded that this was due to the thorough screening for and effective treatment of hypothyroidism among his patients, which largely prevented the development of atherosclerosis. Cancer Barnes claimed there was a strong connection between the hypothyroidism and cancer. He often referred to research showing that tumor transfers in mice will not succeed, unless the thyroid of the receiving mouse is removed first. He also pointed out that given the thyroid's role in immunity, it should not be surprising that depressed thyroid function will depress the bodies ability to fight cancer. Barnes' autopsy research in Graz also informed his view on cancer, noticing that specific forms of cancer exploded after World War II with the introduction of antibiotics. In particular: prostate cancer, lung cancer and cancer in children, all had over a 300% increase per 1000 deaths from 1930 to 1970--occurring mostly in the 25 year period after the war. Barnes concluded that these increases were due to the hypothyroid patient now living long enough to acquire the cancers, whereas previously they didn’t survive the infectious diseases. In the same way as heart attacks, the susceptibility to cancer and infections were concomitant, and the removal of one allowed the other to manifest. Barnes claimed that the cancer rate in his clinic was less than 50% below average, and certain forms of cancer such as lung cancer, were totally absent. Besides hypothyroidism, Barnes also believed that polyunsaturated fats caused cancer. He believed that polyunsaturated fats were not even fit for animals, and that when the association between polyunsaturated fats and cancer was finally exposed, it would "make Watergate look like church social". Depression and Mental Illness Barnes emphasized that mental illnesses are associated with hypothyroidism, especially in the more severe forms. Barnes found that depression in general was a common symptom of hypothyroidism, and was often reversible with thyroid therapy. He also noted that season depression in the colder months was a clue to a thyroid component of depression, as the colder weather puts a higher demand on the thyroid to step up metabolism to keep the body warm. Barnes had concerns that there may be patients in mental institutions who are in fact hypothyroid, but improperly diagnosed. Hypertension Barnes also noticed that a great number of patients with pre-existing hypertension would normalize after thyroid therapy. After reviewing his records, he estimated that thyroid therapy was effective in normalizing blood pressure in approximately 85% of his hypertension patients. Arthritis In Barnes' experience, virtually all patients with arthritis have hypothyroidism. Barnes claimed to have tremendous success in treating arthritis with thyroid therapy, particularly in combination with Predsnisone (5mg-10mg/day). This lead Barnes to conclude that the adrenal glands play an important role in the development of arthritis. Diabetes After many years of practice, Barnes also realized that though he had many diabetic patients, he had not seen virtually a single diabetic complication in his practice. This, along with his previous research into heart disease, lead Barnes to believe that 98% of diabetic patients have a concomitant hypothyroidism. And, when the hypothyroidism in diabetics is properly treated with desiccated thyroid extract, it prevents the atherosclerosis that leads to the various complications seen in diabetics. Hypoglycemia Barnes discovered that 95% of his patients suffering from hypoglycemia, would normalize after proper thyroid therapy. Barnes concluded that in hypothyroidism, the liver is sluggish and unable to meet the demands of converting glycogen to glucose when required, causing blood sugar to drop. By restoring the metabolism of the liver with adequate thyroid, it was then able to properly normalize blood sugar levels. Migraine and Other Headaches After treating a co-worker for hypothyroidism with desiccated thyroid extract, Dr. Barnes was pleasantly surprised when the co-workers' chronic migraine headaches resolved almost completely. This convinced Dr. Barnes that there was a connection between hypothyroidism and chronic severe headaches including migraines, and he proceeded to successfully treat many patients in the same manner over the years. Dr. Barnes claimed a success rate of 95% in treating patients suffering chronic headaches with thyroid therapy. He hypothesized that the swelling that often occurs in hypothyroidism likely elevated the pressure inside the head, leading to these headaches. Susceptibility to Infection Barnes noted that a common feature of Hypothyroidism is a general susceptibility to infection. All infections were more prominent including: sinus infections, respiratory infections, bladder infections etc. Barnes found that when patients hypothyroidism was corrected, their resistance was substantially raised and infections were far less common. Barnes claimed to use antibiotics only 1/10 as much as other physicians because of the proper treatment of hypothyroidism in his practice. Menstrual Disorders and Infertility In Barnes experience, vitually all menstrual disorders were related to hypothyroidism, and would resolve under thyroid therapy. The early and late onset of menses also were highlighted by Barnes as symptoms of low thyroid function. Barnes claimed a high rate of success in treating infertile couples with thyroid therapy. He claimed that most infertile women would become fertile under thyroid therapy, but a small fraction also required adrenal support, usually in the form of Prednisone (5mg/day). Skin Disorders Barnes found that many skin disorders would resolve with thyroid therapy including: acne, dry skin, psoriasis, excema, skin itching & scaly skin. Barnes noted that skin circulation was reduced to as much as 1/4 to 1/5 of normal in advanced hypothyroidism. With this lowered circulation, there is a lowered nourishment and a lowered removal of waste products, leading to lowered resistance and a wide variety of skin diseases. Pregnancy testing The bitterling was shown to respond to hormones in a pregnant woman's urine, but the work was later discredited. In 1932, W. Fleischmann and S. Kann reported in a German gestational physiology journal[14] that female bitterings, small carp-like fish, "show an enlargement of the ovipositor following injection of an estrogenic preparation". Since human pregnancy urine contains estrogen, Drs. Aaron E. Kanter, Carl P. Bauer and Arthur H. Klawans of the University of Chicago added a teaspoon of urine from a pregnant woman to a bowl in which a bitterling was swimming. This experiment produced ovipositor lengthening, as expected by reasoning from the earlier results of Fleischmann. In 1935, Time magazine nationally reported their announcement of this potentially useful new test for human pregnancy, which was then currently determined by rabbit and mouse tests. But subsequent to the announcement, Kanter et al., found that urine from non-pregnant women or men had the same effect. Barnes was the principal investigator, with obstetricians Kanter and Klawans, in an experiment reported in 1936. They sought to determine the source organ of whatever non-pregnant urine substance was causing the same bitterling ovipositor response as Fleischmann's estrogenic preparation. Barnes, et al., extracted juice from 14 different organs of seven species (including both genders of humans) and exposed bitterlings to them. The organ they found responsible was the adrenal cortex.The Barnes, et al., 1936, publication in Science was also reported in Time magazine. In 1938, Fleischmann and Kann determined that in addition to estrogen, a specific adrenal hormone, corticosterone, could cause the observed bitterling ovipositor reaction. This additional non-pregnant hormone reaction made the bitterling test not useful for its originally announced purpose, though it did open the door to an investigation of why corticosterone is significant in urine. Legacy In his last years, Dr. Barnes established a not-for-profit foundation to continue the legacy of his research: Broda O. Barnes Resarch MD, Research Foundation, Inc. . Doctors Supportive of Dr. Barnes Philosophy: Dr. Jeffery Dach, M.D. Dr. Mark Starr, M.D. Dr. David Brownstein, M.D. Dr. Michael Schachter, M.D Dr. Stephan Langer, M.D. Dr. Theresa Hertoghe, M.D. Dr. Thierry Hertoghe, M.D. Dr. Jacques Hertoghe, M.D.

Written by Craig Gustafson, Integrative Medicine: A Clinician's Journal (IMCJ) E. Denis Wilson, MD, will address thyroid function and Wilson’s Temperature Syndrome at the 2015 Restorative Medicine Conference in Blaine, Washington, October 1 through 4. Dr Wilson was the first practitioner to use sustained-release T3 thyroid hormone. For 20 years, he has treated more than 5000 patients with T3 and trained more than 1000 physicians on how to use T3 to improve the health of patients with low thyroid function and low body temperature who have normal blood tests. He is the author of Evidence-Based Approach to Restoring Thyroid Health.1 Integrative Medicine: A Clinician’s Journal(IMCJ): What originally drew your attention to issues of thyroid and metabolism? Dr Wilson: A patient came to my office and she brought with her a book and she said that I should read it. It was called Hypothyroidism: The Unsuspected Illness, by Broda Barnes, MD(2). In that book, he explains the importance of using body temperature as a guide to evaluate thyroid function. I was intrigued by that and also his suggested treatment of using desiccated thyroid as an empirical treatment to normalize the body temperature. Though I did not look at the book for a few weeks, I eventually read it and decided to try his approach in a few of my patients. To my surprise, some of those people got 100% better. That was really illuminating to me because, according to my training in medical school, that was not supposed to happen. These people had normal thyroid blood tests and, supposedly, that meant that they could not benefit from thyroid hormone treatment. These people did not get just a little bit better; they got completely better. It did not work for all the patients I tried it with, but it worked in about 60% of cases. I was looking at the other 40% and wondering how we could help them, too. It could be that they did not have thyroid problems, or maybe the particular treatment I was using was not really addressing their issue. As I was trying to think of ways to increase the yield, I looked at the thyroid hormone pathways and saw that T4 is converted to T3. It turns out that this step is really important. I thought that, perhaps, these patients have a problem with the conversion of T4 to T3. So I started giving some of these treatment failures—these patients who had failed to respond to the pervious treatment—T3 directly. A lot of those treatment failures became treatment successes. That is how it all started. IMCJ: Previous to that, had you been seeing a lot of thyroid patients? Dr Wilson: Not really. I was more involved in primary care practice, but when I started seeing these kinds of thyroid results, the reaction I had was, “If this isn’t true, then perhaps nothing they taught me at medical school is true.” The use of the thyroid hormone blood test to direct thyroid therapy is one of the most dogmatically taught principles in medical school. They acted like the blood tests are absolutely conclusive in managing thyroid health. It was really eye opening to me because this closely held dogma—I could see from my own experience—was not true. Then I thought, “If that is not true, then maybe nothing is true.” That perspective really opens up the possibilities of different things we can try to help people get better. That is when I really started diving in. When the patients do recover, there is hardly anything more dramatic than a hypothyroid patient’s response to thyroid therapy. It can be very pervasive. One thing that I have come to understand over the years is that the purpose of the thyroid hormone is to go into the nucleus of the cell, form transcriptional complexes, and dictate the speed at which DNA is transcribed. It actually dictates how fast we live. That is really what metabolism is. It is how fast we live, which is controlled by the thyroid. When a person asks me what thyroid can affect, I respond, “Thyroid really only affects those cells that have DNA.” In other words, it affects every cell. When I saw the profound ramifications a normal body temperature can have on people, I started doing that pretty much exclusively. IMCJ: What are some of the more frequent symptoms that indicate to you that there may be thyroid dysfunction? Dr Wilson: Certainly fatigue, chronic fatigue, and headaches—migraine headaches. A huge percentage of patients with migraine headaches have low body temperatures and I have seen so many people when they get their temperatures corrected, their migraines sometimes disappear completely. Irritability, fluid retention, anxiety, panic attacks, PMS, hair loss, depression, decreased memory and concentration, low sex drive, unhealthy nails, low ambition and motivation, constipation, easy weight gain for sure, irritable bowel syndrome, dry skin, dry hair, insomnia, and even some things that people wouldn’t normally expect like asthma. Even asthma and hives and allergies can sometimes respond to normalizing a low body temperature. Carpal tunnel syndrome and conditions caused by fluid retention—so there’s a tremendous number of things. Some of my favorites to treat are definitely migraines, PMS, and panic attacks. Panic attacks and anxiety symptoms are very debilitating and they are very responsive to normalizing one’s temperature. That is what makes this so fun to address. There are not many good solutions out there. IMCJ: In many of these cases, the tipping point marker is low body temperature? Dr Wilson: I would say in every case, yes. It is not possible for a person to have symptoms of hypothyroid unless they have a low body temperature. They can have abnormal blood tests and normal temperature and they will still feel fine but the only way you can have those symptoms of hypothyroidism is by having a low temperature. IMCJ: Is the breadth of the symptomatology directly the result of the dysfunctional thyroid or does the low body temperature itself cause secondary symptomatology? Dr Wilson: I believe that it is the temperature itself that causes the symptomatology because the correlation is so complete. My favorite theory has to do with the enzymes we talked about, the transcription of DNA in the nucleus, and that when DNA is transcribed, it makes proteins and enzymes and structural elements. Those enzymes are the key of every chemical reaction in the body and the speed at which those reactions take place and the efficacy of those reactions depend on the enzymes. The whole purpose of an enzyme is to help a reaction take place at a reasonable temperature, like body temperature, when it would not take place at that temperature without it. Without an enzyme, that reaction might not take place at less than 220°F or something like that. With the enzyme, the reaction can take place at a reasonable temperature or a biological temperature. Let’s put it this way: It is known that those enzymes depend on their shape for their activity. The conformation, or the shape of these enzymes, is what brings reacting molecules in close enough proximity to react. If those enzymes are too hot, they are too loose. If they are too cold, they are too tight. If they are just the right temperature, then they are just the right shape. A change in temperature can have a huge impact on the speed of these chemical reactions. IMCJ: How does being “too tight” affect the shape of an enzyme? Dr Wilson: An enzyme is a string of amino acids and it coils upon itself because of the electrostatic charges of the atoms forming a shape. That shape generates active sites where one active site can grab one substrate and another active site can grab another substrate and then, when those substrates are grabbed, the enzyme can change its conformation and bring the reactive species into close proximity so that they can react. All of that depends on temperature, so what I mean by “too tight”—it is like an old-fashioned telephone cord. Sometimes they get tangled like a knot. If you pick the receiver up, the cord untangles and then when you hang it up again, the cord twists up on itself again. That is what I mean by “tight.” If the cord does not tangle up on itself at all, then it is too loose and it does not really work right. If it is too twisted up on itself, then it is too tight and that does not work, either. You want the enzyme to have just the right shape and that depends on temperature. IMCJ: Why are the conventional methods of treating hypothyroid inefficient for resolving these cases? Dr Wilson: It is because the conventional approach is to think that thyroid function—or the adequacy of thyroid function—depends on blood tests. Ever since the thyroid-stimulating hormone, or TSH, test was discovered, or even since they discovered that T4 hormone is converted to T3, there was an assumption made. If you were the one who discovered that T4 is a raw hormone that is converted to T3 and that T3 is actually the active form of thyroid hormone, then at that moment you could make either of 2 conclusions. You could say, “Wow, T4 is converted to T3 and T3 is actually the active hormone. We really shouldn’t focus so much on T4. We should focus more on T3 and the effects of T3 to see if that interaction is adequate—accomplishing what we want it to accomplish.” That is one conclusion. The other conclusion you could make is, “T3 is the active hormone and since the body converts T4 to T3 automatically in the cells of the body, we do not need to worry about that because it happens automatically. The only thing we have to worry about is to ensure that there is adequate T4 production or supply in the blood stream.” Those are 2 reasonable conclusions with very different outcomes. For the last 50 years, the latter of the 2 conclusions has been in favor. Over the last 10 years, research supports the idea that regulation of the conversion of T4 to T3 happens intracellularly and it can change dramatically under different circumstances. That conversion is not measured by a TSH test. The TSH test is not a reliable indicator of thyroid status because the TSH could be normal and a person could still have hypothyroidism in the cells. There is extensive research in the last 10 years, specially, to substantiate that. The T4 to T3 conversion can change under a variety of disease states. Studies of 25 different diseases show that the effects of T4 to T3 conversion can be impaired or can be affected by these different disease states. In these disease states, then, TSH is not a reliable indicator of thyroid status. That is a long answer but the short answer is this: You asked me why the conventional approach to thyroid treatment not very effective and I would just say, “Because they are measuring the wrong thing.” Thyroid blood tests do not measure body temperature. Using the blood test, if 100 people come in with hypothyroid symptoms and these people are treated based on their blood tests, 5% are going to have problems that show up on the blood test. Of those 5% of people with problems identified by the blood test, probably only 50% of those are going to get better with conventional thyroid approach. That is because only 5 people—out of 100 who have low body temperatures that could be effectively managed with treatment—are going to have abnormal blood tests. If you try to get them better by just trying to normalize their blood tests, that is probably only going to work 50% of the time. So, you are only taking about 2.5 people out of 100 who are going to be effectively managed. On the other hand, if you take those 100 people with hypothyroid symptoms, you will find that every one of them has a low body temperature. If you were to treat their temperature, you are going to get 80% to 90% of those people’s temperature to normal. For these 80% to 90%, their symptoms are going to dramatically improve, if not resolve completely. IMCJ: So the crux of the matter is that because the conversion of T4 to T3 is dependent upon an enzyme, there are circumstances—including ambient temperature of the body—that will affect the ability of the enzyme to function or its functional efficiency. That is what the “conventional” approach is missing. Dr Wilson: That is exactly right. If the body worked automatically and always took care of itself, there would be no disease. But there is disease. There are all kinds of diseases. All kinds of things can go wrong with the body and with every aspect of the body. In fact, I am beginning to be of the opinion that anything that happens in the body can go badly. Anything that can go wrong will go wrong in somebody, someplace, at some time, for some reason. If you look down the chemical pathways of the human body, you will see that there is Addison’s disease and there is Cushing’s and there are different diseases that we label based on how things go in the chemical pathways. One really easy way to invent a new condition or new disease is to just find some place in a biochemical pathway where dysfunction has not been named yet and just name it. There has got to be somebody that is going to have a problem in that particular part of the pathway eventually. The deiodinase enzyme depends on selenium and zinc is also important. Of course, if you have a selenium deficiency, T4 to T3 conversion goes down. If you increase selenium in those patients, the T3 levels go up. Obviously, the function of that enzyme is variable under different conditions. It is under regulation and it can be downregulated. This is a really important point. Many of the important pathways to the body are under regulation. That is how we maintain homeostasis and normal functioning of the body. There is something called the ubiquitin proteasome pathway. The way this system works is that key enzymes in different pathways are under regulation. When the body wants to slow down that particular pathway, it downregulates or increases the destruction of that key enzyme. If it wants that pathway to speed up, it will decrease the destruction of that key enzyme so that the pathway can speed up or increase again. The fascinating thing about deiodinase enzymes is that researchers have looked at the things that increase the downregulation of this enzyme. What things shorten the half-life of this enzyme? T4 or thyroxin is 1 of the things and the other is reverse T3. Of course, conventional doctors and alternative doctors, even doctors who treat low body temperature empirically in the face of normal blood testes, will often use desiccated thyroid hormone. Desiccated thyroid hormone contains T4 and, presumably, they are using thyroid hormone because they are thinking that even though the blood tests are normal, the person is not getting enough thyroid stimulation of the cell. They attempt to help the patient by giving the patient more thyroid hormone in the form of desiccated thyroid hormone. Desiccated thyroid hormone has T4, which can significantly downregulate the converting enzyme. A lot of the patients who are treated with Synthroid, or treated with desiccated thyroid, actually do not improve as much as we hoped they would. Sometimes they actually get worse. That is because the T4 in desiccated thyroid can downregulate the enzyme. When that enzyme is downregulated, the T4 gets converted to reverse T3 and both T4 and reverse T3 downregulate that enzyme. Here we are hoping to help the person’s thyroid physiology and help them benefit from more thyroid stimulation of the cell—hoping that we are going to improve their T4 to T3 conversion—and we sometimes actually inadvertently suppress their T4 to T3 conversion and suppress their thyroid hormone stimulation. Thereby, we really do not make the progress that we are looking for. We are giving them this desiccated thyroid and we are not getting their temperatures up. I would encourage doctors, if they are using desiccated thyroid, to have the patient monitor their temperature to make sure it is going up. If temperature is not going up on desiccated thyroid, there may be a good reason for that and it may not work very well for the patient. IMCJ: Will people who benefit from this therapy end up having to continue it forever? Is this something that has a definite treatment duration or is it more a situation where you have to read it by the individual? Dr Wilson: It definitely does depend on the individual. Typically, T3 is not taken for life. There are different problems, which I will address in a second, but the conversion impairment problem—improving T4 to T3 conversion—is something that can normally be corrected in a manner of months. Often the duration is 2 to 3 months, maybe 6, maybe 8, but certainly it is reversible to the point that people do not have to keep taking the treatment for life. I like to separate the thyroid hormone system into 3 different compartments. One is thyroid hormone supply. The second is thyroid hormone conversion and utilization. And the third is thyroid hormone expression. Historically or conventionally, our medical establishment has hoped that they could measure, predict, and manage thyroid hormone expression based exclusively on thyroid hormone supply. We figured that if we just give a person enough thyroid hormone to normalize their TSH, then the thyroid hormone expression will take care of itself and that person will be fine. My opinion is that you cannot measure thyroid hormone expression with a thyroid hormone blood test. Thyroid hormone supply is measured with a thyroid hormone blood test. The TSH is a great measure of thyroid hormone supply but the body temperature is the best measure, as it is an exact measure of thyroid hormone expression. When I say it is an exact measure, what I mean is that the whole purpose of the thyroid system is to determine how fast our bodies live and how fast they function. That is exactly what a thermometer is. A thermometer is literally a speedometer. The higher the kinetic energy of the molecules in the air, the warmer it is outside. As a thermometer actually measures the speed of the molecules in the air, it also measures the speed of the molecules in our bodies. When you measure temperature, you are actually measuring how fast the chemical reactions are taking place in the body. If a person has a normal TSH— they have a normal supply—and they have a low temperature, which is low expression, to me, that logically suggests that they have a problem with thyroid hormone conversion and utilization. If a person has hypothyroidism, has had a thyroidectomy, and has a thyroid hormone supply problem, then, yes, they are going to need thyroid medicine the rest of their life. Without a thyroid gland, they are going to need thyroid hormone to produce supply. Even people who have decent supply might still have a conversion problem. They might still have a low temperature even though they have a normal TSH or even a low TSH. They could actually be hyperthyroid and still have symptoms of hypothyroidism because their temperature is too low. That is because they have a conversion problem. Anyway, to answer your question, the conversion problem is the one that is reversible. For conversion, you can take them off their Synthroid and you could take them off their desiccated and you can give them some herbs and nutrients to support the conversion of T4 to T3 and you can give them T3 directly if they need that. So, there are some things you can do to support thyroid hormone conversion. If you are successful, in that you are going to be able to get their temperature up to normal, lots of times you can wean them off the T3 and, perhaps, put them back on the Synthroid or desiccated thyroid hormone. At that point, they may be able to maintain a normal temperature. With that medicine, they may be able to maintain a normal temperature indefinitely—or maybe in 5 years, or maybe in 10 years they have another relapse and need another tune-up. IMCJ: By getting the body temperature up, a patient then is hopefully creating this enzyme in the right geometry to sustain it on their own? Dr Wilson: Yes. It is just speculation why people tend to get better and seem to stay better. My feeling is that there are a couple of ways to address this thyroid hormone conversion problem. One is with herbs and nutrition. If you properly support the enzyme and the body, then perhaps the enzyme will start functioning better and the conversion improves and the temperature goes up. Even without weaning off Synthroid or without weaning off Armour, sometimes lifestyle, nutritional, and herbal support is enough to improve conversion to the point that they are able to have a normal temperature and to feel well. That is sometimes a good solution and, apparently, you have just supported the converting enzyme. On the other hand, some people are going to need to have their thyroid hormone pathways cleared out. Sometimes, people do not get better until you wean them off the Synthroid and wean them off the desiccated thyroid and replace them for a time with T3 by itself—T3 alone. When you give somebody T3 alone, their TSH goes down and their T4 goes down and their reverse T3 goes down. We have already talked about how strongly T4 and reverse T3 will downregulate the converting enzyme. These can decrease the half-life of the converting enzyme from 40 minutes down to 20 minutes or, in other words 50%, so it can be dramatic. What if, by reducing the T4 and the reverse T3, that that downregulation was relieved and reduced to the point that the deiodinase enzyme could upregulate? Enough to increase to the point that it could restore better T4 to T3 conversion? Some research suggests that there might be a genetic coding problem of the deiodinase enzyme in some people, but I think that, even with normal coding of the deiodinase enzyme, the deiodinase enzyme can get bogged down under periods of stress. And under periods of stress, the conversion of T4 to T3 goes down. That is well known—for decades. When that happens, the reverse T3 goes up. Again, the T4 and reverse T3 can further suppress the deiodinase enzyme, so I feel that this situation can set up a persistent impairment or suppression of the deiodinase enzyme to the point that a person is going to have a hard time maintaining a normal temperature. IMCJ: Then is there any direct evidence at this point that the stress hormone, cortisol, interferes with the process directly? Dr Wilson: Yes. Cortisol has been shown to directly inhibit the conversion of T4 to T3 for sure. One other thing: I do want to make it clear that I do not mean reverse T3 on a blood test. I am not saying that measuring reverse T3 in a blood test is going to be useful at all, because I haven’t found it to be. I have not found it to be predictive or reliable. Some people with lower reverse T3 levels still have low body temperatures. You can have a person with low TSH, which makes them look like they are hyperthyroid, and then they have a high total T3, which makes them look like—if anything—they are making plenty or too much T3, and they could have a low reverse T3, which makes them look like if anybody is converting T4 to T3 very well, it is this person. They could still have low temperature regardless of anything that the blood tests say. I still think that they could have impaired conversion at the level of the cell that is invisible on the blood test. The blood tests do not measure what is happening inside the cell. They only measure what is floating around in the blood stream. IMCJ: To wrap things up, when you speak at the Restorative Medicine Conference in October, what more are people going to learn at your presentation? Dr Wilson: I will talk about the specifics of the nutritional and herbal support. I will talk about the specifics of T3 therapy and how to monitor and manage patients. Basically, they will learn how to normalize somebody’s body temperature in a way that will help patients recover from their symptoms and hopefully remain improved even after their symptoms have been discontinued. For more information about the 2015 Restorative Medicine Conference, please visit http://www.restorativemedicine.org/. References 1. Wilson ED. Evidence-based Approach to Restoring Thyroid Health. Lady Lake, FL: Muskeegee Medical Publishing Company; 2014. [Google Scholar] 2. Barnes B. Hypothyroidism: The Unsuspected Illness. New York, NY: Harper; 1976. [Google Scholar]

Written by Dr. John C. Lowe as a response to Peter Warmingham, BSc (Hons), MIET and his paper on the topic with the same title (below). Many examples in the history of science show that landmark advances in particular scientific fields often come from specialists in other fields. I firmly believe this is the case with Peter Warmingham and his hypothesis about the conventional error of using the TSH to adjust patients' dosages of thyroid hormone during their treatment for hypothyroidism. As a way to introduce Peter Warmingham, I will briefly mention one of the many examples of landmark changes in scientific fields brought about by the thinking of specialists in other fields. Alfred Wegener is now recognized as the founding father of one of the major scientific revolutions of the 20th century, the concept of continental drift and plate tectonics. His hypothesis of continental drift came to him in 1912 and he announced the hypothesis in 1915. In the hypothesis, Wegener argued that all continents were once joined together in a single landmass and have drifted apart. His book on the theory was published in the US in 1925. Its appearance set off vehement opposition by prominent geological scientists. Some of them disdainfully dismissed Wegener's hypothesis using the logical fallacy called ad hominem; that is, rather than debating the evidence he presented, they argued that he was wrong because he was not a geologist. This was true: Wegener was an astronomer who specialized in meteorology and climatology. I mention Wegener and the logical fallacy used to denounce his hypothesis because I anticipate the same fate for Mr. Warmingham's hypothesis. The endocrinology specialty often uses the logical fallacy when researchers or clinicians not board certified in endocrinology present evidence that conventional beliefs of the endocrinology specialty are false. For example, when Dr. Steven Hotze challenged Dr. Bill Law (at the time President of the American Association of Clinical Endocrinologists) to debate on national television desiccated thyroid vs levothyroxine, Dr. Law declined. Among his reasons was that only board certified endocrinologists, which Dr. Hotze was not, are qualified to publicly comment on the treatment of hypothyroidism. If ad hominem is used to denounce the "Warmingham TSH Hypothesis," as I call it, I want our subscribers to recognize the fallacy and to appreciate its total irrelevance to whether or not the Warmingham hypothesis is right or wrong. Intense opposition to Wegener's theory continued into the 1950s. But by the 1960s, accumulated scientific evidence showed that Wegener had been right. At the same time, it showed that prominent geological scientists who had scorned his theory were wrong. Modern plate tectonics is the direct descendent of Wegener's theory of continental drift. Today, plate tectonics is a thriving and productive scientific field. And humanity benefits from this field for a reason important to note: largely because Wegener's knowledge of scientific fields other than geology gave him a parallactic view of the origin of continents — a view that correctly meant that the contrary views of geologists had to be wrong. His parallatic view—rebuked by many because he was not a geologist—seeded the scientific soil for the fruitful growth of the science of geology from the 1960s on. Examples such as Wegener's lead me to value proferted intellectual insights from those in fields other than thyroidology who nevertheless are knowledgeable in various aspects of thyroidology. Peter Warmingham is an exemplary example. He is an electrical and electronics engineer with special knowledge of control systems. The pituitary-thyroid axis is a biological control system, one which Mr. Warmingham clearly understands. His landmark hypothesis shows how a facility essential for successful performance in engineering—that is, exacting precision in analytical thought—has enabled him to see clearly what so many thyroidologists have long failed to see. Mr. Warmingham's hypothesis is straightforward: When a hypothyroid patient (whose circulating pool of thyroid hormone is too low) begins taking exogenous thyroid hormone, a negative feedback system reduces the pituitary gland's output of TSH. This decreases the thyroid gland's output of endogenous thyroid hormone, and despite the patient's exogenous thyroid hormone's contribution to his or her total circulating thyroid pool, that pool does not increase—not until the TSH is suppressed and the thyroid gland is contributing no more thyroid hormone to the total circulating pool. At that point, adding more exogenous thyroid hormone will finally increase the circulating pool of thyroid hormone. The increase must occur for thyroid hormone therapy to be effective. The patient's suppressed TSH, then, does not indicate that the patient is over-treated with thyroid hormone; instead, it indicates that the patient's low total thyroid hormone pool will finally rise to potentially adequate levels. The implication of the Warmingham TSH Hypothesis is clear: In general, if the clinician denies the patient more exogenous thyroid hormone because his or her TSH level is suppressed, the clinician will deny the patient enough thyroid hormone to increase the circulating pool of the hormone to a level adequate for maintaining normal thyroid hormone-driven cellular metabolic processes. But if the clinician continues to increase the patient's thyroid hormone dosage based on relevant measures of physiological function, such as the basal temperature, then the patient's health will be properly served despite his or her suppressed TSH level. With this introduction, Thyroid Science presents to our subscribers what we believe to be a hypothesis of supreme importance to the proper treatment and health and well-being of hypothyroid patients. The original paper:

Written by Hussein Abdel Hai El Orabi, Inas Mohamed Sabry, Ahmed Mohamed Awad Allah, Alshymaa Alsayed Abd Alkhalek, March 21, 2010 (Department of Internal Medicine; Endocrine Unit; Department of Gynecology and obstetric, Ain Shams University; Cairo, Egypt Abstract Background Several studies have suggested that hyperemesis gravidarum in early pregnancy is related to women’s levels of thyroid hormones, human chorionic gonadotropin (hCG), and serum leptin. To ascertain this relationship, we investigated 50 pregnant women in the first trimester. Twenty subjects had morning sickness, 20 had hyperemesis gravidarum, and 10 were healthy pregnant women who served as control subjects. Methods The enzyme immunoassay method was used to measure all subjects’ serum levels of T3 (pg/mL), T4 (ng/dL), TSH (μIU/mL), antithyroid peroxidase (anti-TPO) antibodies (IU/ml), and leptin (ng/mL). Serum β hCG was quantitatively assayed. Results There was a statistically significant difference between the three studied groups as regards serum free T4 (p < 0.05), but there was no difference as regards serum free T3 , TSH, anti-TPO, and serum β-hCG (p > 0.05). Serum leptin was significantly higher (p < 0.001) in the hyperemesis gravidarum and vomiting group compared to the healthy control group, with a non significant difference between pregnant women with hyperemesis gravidarum and those with vomiting (p >30.05). Correlation analysis showed that the only significant positive correlation was between serum T3 and serum leptin (p < 0.05) in hyperemesis gravidarum. No significant correlation was found between β-hCG and thyroid hormones, antithyroid antibodies, and serum leptin in pregnant women with morning sickness and hyperemesis gravidarum (p > 0.05). Conclusion Our results suggest that serum leptin levels are involved in the pathogenesis of hyperemesis gravidarum. No significant role was detected for thyroid hormones, serum β-hCG, or anti-TPO in patients with hyperemesis gravidarum. Keywords • Hyperemesis gravidarum • hCG • Leptin • Pregnancy • T3 • T4 • Thyroid hormone INTRODUCTION Hyperemesis gravidarum is a condition of intractable vomiting during pregnancy, leading to fluid, electrolyte and acid–base imbalance, nutritional deficiency, and weight loss often severe enough to require hospital admission. Hyperemesis gravidarum is[1] most prevalent during, but certainly not limited to, the first trimester of pregnancy when both the placenta and the corpus luteum are producing hormones and the body is adapting to the pregnancy state. [2] Estimates of the incidence of hyperemesis gravidarum vary from 0.3 to 1.5% of all live births, with most authors reporting an incidence of 0.5%. It is [3,4] said to be higher in multiple pregnancies, hydatidiform mole, and other conditions associated with increased pregnancy hormone levels. [2] Up to 80% of all pregnant women experience some form of nausea and vomiting during their pregnancies. Because the great majority of pregnant [5] women experience discomfort due to nausea and vomiting, a functional role of nausea and vomiting is often considered. Despite decades of research, the cause of these conditions remains unknown, and the relationship between nausea and vomiting during pregnancy and hyperemesis gravidarum is still unclear. Many [2] etiopathogenic factors have been considered for hyperemesis gravidarum, including endocrine factors, hepatic dysfunction, changes in lipid metabolism, upper gastrointestinal system dysmotility, and psychological factors. However, no specific causative factor has been established. Theories on how pregnancy [6] hormones could cause hyperemesis gravidarum assert that patients who develop the condition may be exposed to higher levels of hormones during early pregnancy, especially progesterone and hCG. Also, irrespective of the gestational week, the rapid increase in the leptin concentrations in the first trimester may be a factor and also an early marker for hyperemesis gravidarum. [6] Sometimes, thyroid hormone values deviate from the reference range, leading to a state referred to as gestational transient thyrotoxicosis (GTT). This has been observed in up to two thirds of women suffering from hyperemesis gravidarum. [7] The etiology of transient hyperthyroidism of hyperemesis gravidarum is unclear. Some have argued that the hyperthyroidism is the cause of hyperemesis, whereas others have argued the reverse. The aim of this study was to evaluate the thyroid function, serum β-hCG, and serum leptin in women with hyperemesis gravidarum. MATERIALS AND METHODS A case-control study was conducted involving 50 pregnant women in their first trimester of pregnancy. The women were selected from the outpatient clinic of Maternity Clinic and the in-patient wards of the Hospital of Obstetric and Gynecology at Ain Shams University Hospitals. The patients were divided into three groups. The first group was patients with emesis (vomiting); the second group was patients with hyperemesis gravidarum [defined as persistent nausea and vomiting associated with ketosis and weight loss > 5% of pre-pregnancy weight]; and the third group [8] was healthy pregnant women who served as controls. All groups were adjusted for age, parity, and BMI. All included women were subjected to the following: full history taking, thorough clinical examination; measurement of serum TSH (μIU/mL) by electrochemiluminescence immunoassay (ECLIA); serum FT3 (pg/mL), serum FT4 (ng/dL), and anti-thyroid peroxidase (Anti-TPO)(IU/mL) by micro particle enzyme immunoassay (MEIA); serum β-human chorionic gonadotrophins (serum β-hCG) quantitatively by the Sandwich principle; serum leptin (ng/mL) by ELISA technique (normal value of serum leptin level is: < 50 ng/ml); and blood urea (mg/dL), serum creatinine[9] (mg/dL), serum sodium (mmol/l), serum potassium (mmol/L), and complete blood picture to detect the severity of emesis. A blood sample of 15 cc was withdrawn from each subject and the blood sample was divided in the following way: (a) 5 cc were used for a thyroid profile (TSH, FT3 , FT4, and Anti-TPO); (b) 5 cc were were collected and stored as serum in an aliquot at -20°C till time of assay for serum leptin. (c) 5cc were used for blood electrolytes and urea, and serum creatinine and β-hCG (quantitative). Also, ketones in a morning urine sample were measured with urine stripes. Statistical Analysis Data were collected, revised, verified, and then edited on a PC. Then data were analyzed statistically using SPSS statistical package, version 15. Data were expressed as mean ± SD for quantitative measures. The following tests were done: 1. The Student’s-t test for independent variables and was used to assess significant differences between values in various groups of patients where appropriate. 2. ANOVA test was used for comparison between more than two independent groups as regard studied variables. 3. Post hoc test was used for comparison of quantitative variables. 4. Pearson correlation coefficient (r) was done for correlations between different studied parameters. 5. Sensitivity, specificity, and diagnostic accuracy at different cut-off levels and ROC-curves were analyzed. The results were considered to be statistically significant at a p value of < 0.05, highly significant at p value of < 0.001, and insignificant at a p value of > 0.05. RESULTS As shown in Table 1, the only statistically significant differences between the three studied groups were in regard to the free T4 and serum leptin (p < 0.05). The β-hCG level was higher in patients with hyperemesis gravidarum than in women with emesis and healthy controls, but the difference was not significant (p > 0.05). Post hoc testing for comparisons of the three studied groups showed a significantly higher mean free T4 level for group 2 compared to group 1 and group 3 (p < 0.05). But as shown in Table 2, the difference in the free T4 level between group 1 and group 3 was not significant (p > 0.05). Also, the difference in leptin levels between the the emesis group and the hyperemesis gravidarum group was not significant (p > 0.05). However, the leptin levels in both the emesis group and hyperemesis gravidarum group were highly significantly higher than the level in the healthy control group (p < 0.00). Pearson correlation tests for the emesis group and the healthy control group, respectively, showed no significant correlation of serum leptin and serum β-hCG (r: 0.107) (r: 0.198), anti-TPO (r: 0.029) (r: -0.590), free T3 (r: 0.145) (r: 0.287), and free T4 (r: 0.322) (r: -0.374) (p > 0.05). In the hyperemesis gravidarum group, the serum leptin level was positively correlated with the free T3 with an r value of 0.551. In the healthy control group, the leptin level was significantly negatively correlated with the serum TSH (r = -0.737, p < 0.05). Also, in this group, the serum β-hCG level was positively correlated with the free T3 level (r = 0.755, p <0.05). In the emesis group and the hyperemesis gravidarum group, respectively, no correlation (p > 0.05) was found between the levels of serum β-hCG and anti-TPO (r: -0.146) (r: 0.021), serum leptin (r: 0.367( (r: 0.107) [Figure 2], TSH (r: 0.344) (r: -0.212), free T4 (r: -0.248) (r: -0.312), and free T3 (r: 0.050) (r: -0.359). Serum anti-TPO was positively correlated only with the free T3 (r: 0.587) and the free T4 (r: 0.938) in hyperemesis gravidarum group (p < 0.01) and the TSH (r: 0.447) in the emesis group (p < 0.05). For the hyperemesis gravidarum group, the ROC curve detected the best cutoff point for the free T4 : 1.06 ng/dL, with a sensitivity = 80% and a specificity = 80 % and an area under the curve of 0.743 with a p value of < 0.004. But there was not a significant cut off point for serum leptin with a p value of > 0.05, a sensitivity = 60%, and a specificity = 53.3%. DISCUSSION Hyperemesis gravidarum is defined as excessive vomiting during pregnancy, which may lead to sever outcomes including weight loss, dehydration, fasting acidosis, alkalosis due to hydrochloric acid loss, and hypokalemia. Both the etiology and pathogenesis of [10] hyperemesis gravidarum remain unknown. The potential [2] role of pregnancy-related hormones such as progesterone, estrogen, and hCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid hormone, and adrenal-cortical hormones have been implicated in the etiology of hyperemesis gravidarum. The presence of an association between hyperemesis gravidarum and the rapid increase in leptin of placental origin, particularly in the first trimester, may be considered. This study aimed to study thyroid [6] hormones, serum β-hCG, anti-TPO, and serum leptin in women with hyperemesis gravidarum, and to detect any possible role of these parameters in the pathogenesis of hyperemesis gravidarum. Our study revealed that there was no significant difference between the three studied groups as regards the free T3, TSH, and anti-TPO (p > 0.05). Only the free T4 was significantly higher in the hyperemesis gravidarum group compared with the emesis group and the healthy control group (p < 0.05). However, the higher free T4 was still within reference range. The higher reference range free T4 level in the hyperemesis gravidarum group can be explained by the characteristic pattern of serum free T4 changes during normal pregnancy. This pattern includes a slight and temporary rise in the free T4 during the first trimester (due to the thyrotropic effect of hCG) and a tendency for serum free T4 values to decrease progressively during later gestational stages. But, although we found that the [11] serum β-hCG level was higher in the hyperemesis gravidarum group than in the emesis group and the healthy control group, the level was not significantly different (p > 0.05). This finding agrees with Al-Yatama et al. They [12] found that the serum free T4 level was higher in hyperemesis gravidarum patients than in healthy controls (p < 0.0001), but no patients showed signs of thyrotoxicosis. We detected that the best significant cut off point of free T4 for women with hyperemesis gravidarum was 1.06 ng/dL with a sensitivity = 80% and a specificity = 80% with a p value of < 0.004), which is still within the reference range for the free T4 . Panesar et al. found by logistic regression analysis[13] that the free thyroxine level was an independent variable. In addition, they found no significant difference between the free T4 levels of healthy pregnant women and those with emesis (p > 0.05). Kimura et al. found that serum free T4 and free T3 levels were[14] higher in pregnant women with emesis and hyperemesis gravidarum (p < 0.01) and that the serum TSH was suppressed to less than 0.1mU/L in both groups. They also found, as we did in this study, that the serum β-hCG level did not significantly differ between the emesis group, hyperemesis gravidarum group, and the healthy control group. Also, Wilson et al. [15] reported no significant difference between the thyroid hormone and hCG levels of healthy controls and hyos peremesis gravidarum patients. In addition, Panesar et al. observed that hGC is not independeetiology of [13] hyperemesis gravidarum. In contrast, however, Al-Yatama et al. reported that the total β-hCG level [12] was significantly higher in hyperemesis gravidarum patients than in healthy control subjects. Tan et al. found that hyperemesis gravidarum [16] patients were not clinically overtly thyrotoxic and thyroid antibodies were usually absent. But Taskin et al. reported that the serum TSH and serum β-hCG [17] levels were higher in women with hyperemesis gravidarum than in healthy pregnant women, while there was no significant difference between the groups as regards free T3 and T4 levels. However, Asakura et al. found that free T3 and free T4 levels were significantly [18] higher in hyperemesis gravidarum patients than in healthy controls; the levels were higher in the hyperemesis gravidarum patients with milder symptoms of morning sickness (p < 0.05). Also, Leylek et al. found that the mean serum hCG, free T3, and [19] free T4 levels were significantly higher in hyperemesis gravidarum patients than in healthy controls (p < 0.05), with a non-significant difference in serum TSH levels (p > 0.05). They also found that for hyperemesis gravidarum patients, the serum hCG significantly negatively correlated with the TSH and positively correlated with the free T3 and free T4. They found no relationship between β-hCG and thyroid function test levels in the control group (p > 0.05). Our study did not show a significant correlation between serum β-hCG and serum TSH, free T3, and free T4 levels in hyperemesis gravidarum patients. In healthy controls, only the β-hCG level was positively correlated with the free T3 (r = 0.755, p < 0.05). Tareen et al., demonstrated that serum T4 and β-hCG [20] were significantly increased in hyperemesis gravidarum, while the TSH significantly declined in the same group. They also found a direct relationship between the serum T4 and β-hCG levels and an inverse relationship between the TSH and β-hCG levels in pregnant women with morning sickness. Goodwin et al. observed that the hCG level [21] correlated directly with the free T4 level and inversely with the TSH level (p < 0.001) in women with hyperemesis gravidarum. They also found that patients with hyperemesis gravidarum had significantly higher mean levels of free T4, hCG, and total T3, and a lower TSH level compared to control subjects. From these results, it was suggested that hyperemesis gravidarum may be caused by some not-yet-identified circulating stimulator. Abell and Riely, suggested that there is [22] a circulating hormone or hormone-like substance that may stimulate the thyroid gland and render it temporarily unresponsive to the control of the pituitary. This suggests that thyroid hormones are stimulated by something other than the TSH. By the time this substance subsides in later pregnancy, both the hyperemesis gravidarum and the hyperthyroidism resolve. The serum leptin levels significantly differed (p < 0.00) between our three studied groups: the emesis and hyperemesis gravidarum groups had higher leptin levels than the healthy control group. However, the difference between women with emesis and hyperemesis gravidarum was not significant (p > 0.05). This agrees with Nurettin et al. who found that their group with hyperemesis gravidarum had significantly a higher serum leptin level (p = 0.037) than healthy pregnant women. But thyroid hormones and hCG levels in the two groups did not significantly differ. In the hyperemesis gravidarum group in our study, only the serum leptin level positively correlated with the free T3 level (p < 0.05). But three prospective cohort studies that compared the serum leptin levels between hyperemesis gravidarum patients and controls did not show a statistically significant difference. Supporters of the leptin theory stated that [23,24,25] this could be a false negative finding due to a negative energy balance in hyperemesis gravidarum patients, a dramatic decrease in leptin levels being observed in other condition with a negative energy balance, such as fasting [26,27,28]. Our data show that patients with hyperemesis gravidarum had a significantly higher free T4 level, but the level was within the reference range and the patients had no clinical manifestations of thyrotoxicosis. The group therefore had no underlying thyroid abnormality. It appears that neither thyroid hormones nor hCG contribute to the pathogenesis of hyperemesis gravidarum. Serum leptin, however, may play a role in the pathogenesis of hyperemesis gravidarum. Larger studies are needed to confirm this role. REFERENCES 1. Fairweather DV: Nausea and vomiting in pregnancy. Am. J. Obstet. Gynecol., 102,135–175, 1968. 2. Verberg, M.F., Gillott, D.J., Al-Fardan, N., et al.: Hyperemesis gravidarum, a literature review. Hum. Reprod. Update, 11(5):527-539, 2005. 3. Kallen, B.: Hyperemesis during pregnancy and delivery outcome: a registry study. Eur J Obstet Gynecol. Reprod. Biol., 26:291–302, 1987. 4. Tsang, I.S., Katz, V.L., and Wells, S.D.: Maternal and fetal outcomes in hyperemesis gravidarum. Int. J. Gynaecol. Obstet., 55,231–235, 1996. 5. Gadsby, R., Barnie-Adshead, A.M., and Jagger, C.: A prospective study of nausea and vomiting during pregnancy. Br. J. Gen. Pract., 43,245–248, 1993. 6. Nurettin, A.K.A., Sacide, A., Sayharman, S., et al.: Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum. Aust. N.Z. J. Obst. Gyn., 46:247-277, 2006. 7. Goodwin, T.M., Montoro, M., and Mestman, J.H.: Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am. J. Obstet. Gynecol., 167,648–652, 1992. 8. Goodwin, T.M.: Hyperemesis gravidarum. Obstet. Gynecol. Clin. North Am., 35(3):401-417, 2008. 9. Blum, W.F., Englaro, P., Hanitsch, S., et al.: Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J. Clin. Endocrinol. Metab., 82(9):2904-2910, 1997. 10. Kuscu, N.K. and Koyuncu, F.: Hyperemesis gravidarum: current concepts and management. Postgrad. Med. J., 78(916):76-79, 2002. 11. Kurioka, H., Takahashi, K., and Miyazaki, K.: Maternal thyroid function during pregnancy and puerperal period. Endocr. J., 52:587, 2005. 12. Al-Yatama, M., Diejomaoh, M., Nandakumaran, M., et al.: Hormone profile of Kuwaiti women with hyperemesis gravidarum. Arch. Gynecol. Obstet., 266,218–222, 2002. 13. Panesar, N.S., Li, C.Y., and Rogers, M.S.: Are thyroid hormones or hCG responsible for hyperemesis gravidarum? A matched paired study in pregnant Chinese women. Acta Obstet. Gynecol. Scand., 80:519–524, 2001. 14. Kimura, M., Amino, N., Tamaki, H., et al.: Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin. Endocrinol. (Oxf), 38,345–350, 1993. 15. Wilson, R., McKillop, J.H., MacLean, M., et al.: Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum. Clin. Endocrinol. (Oxf), 37:331–334, 1992. 16. Tan, J.Y., Loh, K.C., Yeo, G.S., et al.: Transient hyperthyroidism of hyperemesis. BJOG Jun., 109(6):683-688, 2002. 17. Taskin, S., Taskin, E.A., Seval, M.M., et al.: Serum levels of adenosine deaminase and pregnancy-related hormones in hyperemesis gravidarum. J. Perinat. Med., 37(1):32-35, 2009. 18. Asakura, H., Watanabe, S., Sekiguchi, A., et al.: Severity of hyperemesis gravidarum correlates with serum levels of reverse T3 . Arch. Gynecol. Obstet., 264:57–62, 2000. 19. Leylek, O.A., Cetin, A., Toyaksi, M., et al.: Hyperthyroidism in hyperemesis gravidarum. Int. J. Gynaecol. Obstet., 55:33–37, 1996. 20. Tareen, A.K., Baseer, A., Jaffry, H.F., et al.: Thyroid hormone in hyperemesis gravidarum. J. Obstet. Gynaecol., 21:97–501, 1995. 21. Goodwin, T.M., Montoro, M., Mestman, J.H., et al.: The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J. Clin. Endocrinol. Metab., 75:1333–1337, 1992. 22. Abell, T.L. and Riely, C.A.: Hyperemesis gravidarum. Gastroenterol. Clin. North Am., 21(4):835-849, 1992. 23. Arslan, E.O., Cengiz, L. and Arslan, M.: Thyroid function in hyperemesis gravidarum and correlation with serum leptin levels. Int. J. Gynaecol. Obstet., 83:87–188, 2003. 24. Lee, J., Lee, K., Kim, M., et al.: The correlation of leptin and hCG (Human Chorionic Gonadotrophin) levels in the serum between women with hyperemesis gravidarum and normal control. Fertil. Steril., 80(Suppl. 3):S251–S252, 2003. 25. Unsel, N., Benian, A., and Erel, C.T.: Leptin levels in women with hyperemesis gravidarum. Int. J. Gynaecol. Obstet., 84:162–163, 2004. 26. Boden, G., Chen, X., Moxxoli, M., et al.: Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab., 81: 3419–3423, 1996. 27. Kolaczynski, J.W., Considine, R.V., Ohannesian, J., et al.: Responses of leptin to short-term fasting and refeeding in humans. A link with ketogenesis but not ketones themselves. Diabetes, 45:1511–1515, 1996. 28. White, D.W., Wang, D.W., Chua, S.C. Jr., et al.: Constitutive and impaired signaling of leptin receptors containing the Gln –> Pro extracellular domain fatty mutation. Proc. Natl. Acad. Sci. (USA), 94:10657–10662, 1997.

Written by Dr. John C. Lowe, March 8, 2010 Women often contact us to express a common concern. Their doctors have told them that their high anti-thyroid antibody levels are of no importance to their health. The women also tell us how their doctors justify this belief to them: “You’re ‘euthyroid,’ the doctors explain. “That means your TSH is ‘in range.’ And when your TSH is in range, your thyroid function is just fine. So don’t worry about the antibodies.” But two groups of women do remain concerned; some of them are even fearful. Most of the women in both know that high anti-thyroid antibodies mean they have autoimmune thyroid disease. They also have read enough to know that an in-range TSH level is no assurance whatever that a person has enough thyroid hormone regulation to be healthy. One group of the women is concerned about their high anti-thyroid antibody levels because they aren’t able to get pregnant. They fear that their autoimmune thyroiditis is responsible for their infertility. The second group of women remain concerned about their high anti-thyroid antibodies because they’ve had troubled or failed pregnancies. They, too, suspect that autoimmune thyroid disease is responsible. I’ll be forthright and say here that both groups of women do indeed have good reason for concern over their anti-thyroid antibody levels. Below I support this proposition by briefly reviewing some of the relevant evidence. That evidence, to give a more specific proposition, shows this—even in women with in-range TSH and thyroid hormone levels, high anti-thyroid antibodies are associated with both infertility and complicated and failed pregnancies. Ovarian stimulation and in vitro fertilization. In 2009, Italian researchers wrote, “Anti-thyroid antibodies, even if not associated with thyroid dysfunction, are suspected to cause a poorer outcome of in vitro fertilization.” They analyzed patients’ records for the prevalence of autoimmune thyroiditis among infertile women who had reference range TSH and thyroid hormone levels. The prevalence of high antibodies in euthyroid women was 10.5%. Some of the women with autoimmune thyroiditis didn’t undergo thyroid hormone therapy. Compared to control women, these untreated women didn’t respond as well to ovarian stimulation and in vitro fertilization. The researchers noted that women who used T4 responded better to ovarian stimulation. However, they responded no better to in vitro fertilization than did women with autoimmune thyroiditis who didn’t undergo thyroid hormone therapy. But women who were treated with combined thyroid hormone, aspirin, and prednisolone responded as well to in vitro fertilization. In fact, they responded as well as women who didn’t have autoimmune thyroiditis. The findings from this Italian study support the 2008 findings of Spanish researchers.[6] These researchers found that women with implantation failure had a higher incidence of both thyroid peroxidase (TPO) and anti-thyroglobulin antibodies—despite the patients’ TSH and free T4 levels being in-range. The Spanish researchers also found that both types of anti-thyroid antibodies were higher in women with “unexplained infertility” than in women with recurrent spontaneous abortion. (This is an important finding in that women with recurrent spontaneous abortion also have a high incidence of anti-thyroid antibodies.[3,4,5]) And once more, the women with unexplained infertility had in-range TSH and free T4 levels. The Spanish researchers wrote that thyroid autoimmunity in euthyroid women is “strongly” related to both unexplained infertility and implantation failure.[6] Euthyroid autoimmune thyroiditis. In a review 2009 paper,[1] Dr. R. Gärtner pointed out that women who are euthyroid but have high thyroid peroxidase antibodies more often have miscarriages, preterm deliveries, and postpartum thyroiditis. (He believes that if these euthyroid women begin taking T4 early in their pregnancies, they’re less likely to have pregnancy complications.) Indeed, whether the women are euthyroid or hypothyroid, if they have high anti-thyroid antibodies, they are more susceptible to reproductive problems. In 2000, researchers in Greece found that compared to control women, women with recurrent spontaneous miscarriage had a higher incidence of high anti-thyroid antibodies.[3] In 2004, Israeli researchers found a statistically significant association between thyroid peroxidase antibodies recurrent miscarriages[4] And in 2008, Iranian researchers reported that compared to controls, women with recurrent spontaneous abortions had a significantly higher incidence of both thyroid peroxidase and anti-thyroglobulin antibodies. They concluded, “. . . thyroid autoimmunity was independently associated with a higher risk of recurrent abortion.”[5] Subclinical hypothyroidism Dr. Gärtner noted[1] that if a pregnant mother isn’t euthyroid but has subclinical hypothyroidism, this may impair normal development of the fetus. The mother, he wrote, should undergo thyroid hormone therapy even when her TSH is within the upper end of the reference range. And again, for emphasis perhaps, he wrote, “Special care is necessary in women with elevated TPO antibodies, because these [women] more often develop postpartum thyroiditis.” Conclusion The research literature contains sufficient evidence that high anti-thyroid antibodies are associated with infertility and troubled pregnancies. Because of this, in my opinion, if you’re a euthyroid woman with high anti-thyroid antibodies, and you’re concerned that these may be associated with your infertility or problematic pregnancies, your concern is warranted. Let your concern motivate you. If you want to continue working with your current clinician who has been mistaken about the issue, then share the research I’ve cited in this article with him or her. Hopefully he or she will cooperate with you so as to relieve your concerns. If not, however, let your concern motivate you to find another clinician who will cooperate with you. In either case, work with the clinician you choose to relieve any health problems you have related to your autoimmune thyroiditis—and especially, of course, any reproductive problems you have. References 1. Gärtner, R.: Thyroid disorders during pregnancy. Dtsch. Med. Wochenschr., 134(3):83-86, 2009. (Medizinische Klinik Innenstadt der Universität München. roland.gaertner@med.uni-muenchen.de2.) 2. Revelli, A., Casano, S., Piane, L.D., et al.: A retrospective study on IVF outcome in euthyroid patients with anti-thyroid antibodies: effects of levothyroxine, acetyl-salicylic acid and prednisolone adjuvant treatments. Reprod. Biol. Endocrinol., 7:137, 2009. (Reproductive Medicine and IVF Unit, Department of Obstetrical and Gynecological Sciences, University of Torino, OIRM-S, Anna Hospital, Torino, Italy. fertisave@yahoo.com.) 3. Dendrinos, S., Papasteriades, C., Tarassi, K., et al.: Thyroid autoimmunity in patients with recurrent spontaneous miscarriages. Gynecol. Endocrinol., 14(4):270-274, 2000. (Second Department of Obstetrics and Gynecology, University of Athens, Greece.) 4. Marai, I., Carp, H., Shai, S., et al.: Autoantibody panel screening in recurrent miscarriages. Am. J. Reprod. Immunol., 51(3):235-240, 2004. (Department of Medicine 'B', Center for Autoimmune Diseases, Sackler Faculty of Medicine, Tel-Aviv University, Tel Hashomer, Israel.) 5. Iravani, A.T., Saeedi, M.M., Pakravesh, J., et al.: Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study. Endocr. Pract., 14(4):458-464, 2008. (School of Medicine, Medical Sciences/University of Tehran, Tehran, Iran. Iravani_amir@yahoo.com.) 6. Bellver, J., Soares, S.R., Alvarez, C., et al.: The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum. Reprod., 23(2):278-284, 2008. (Instituto Valenciano de Infertilidad (IVI), University of Valencia, Plaza de la Policía Local, 3, 46015 Valencia, Spain. jbellver@ivi.es.)

Written by Dragana Jokic, MD and Xiangbing Wang, MD, PhD, July 13, 2011 Abstract Objective: Our purpose is to report a case of primary hypothyroidism associated with hyperprolactinemia and pituitary macroadenoma. Background: We present the case report, including detailed laboratory and radiological findings in a 28-year-old woman. In primary hypothyroidism there is hyperplasia of both thyrotrophs and lactotrophs as a response to TRH hypersecretion. The hyperplasia can result in significant enlargement of the pituitary gland and can be mistaken for a prolactin-secreting tumor. Case: We report the case of a female patient who presented with amenorrhea of 7 months duration and was found by her gynecologist to have elevated prolactin. The initial MRI showed a 1.7 cm pituitary mass which was treated initially by cabergoline. Due to the patient’s noncompliance and lack of follow up, the patient remained on cabergoline for 6 months and did not do thyroid function tests. Finally, after 6 months, a follow up MRI showed no change in size of her pituitary mass. Also, blood tests showed profound hypothyroidism, and after 6 month of thyroid replacement therapy, the patient was euthyroid. A repeated MRI of the brain showed complete resolution of the pituitary mass. Result: This case emphasizes the importance of evaluation of thyroid function in cases of elevated prolactin and gonadal dysfunction. Despite a lack of the typical clinical presentation of hypothyroidism, resolution of the patient’s symptoms and disappearance of her pituitary macroadenoma confirms the diagnosis. Conclusion: This case illustrates that primary hypothyroidism can present with amenorrhea and pituitary mass. Introduction Prolactin is a pituitary-derived hormone that plays a pivotal role in a variety of reproductive functions. Prolactin negatively modulates the secretion of pituitary hormones responsible for gonadal function, including luteinizing hormone and follicle-stimulating hormone. An excess of prolactin, or hyperprolactinemia, is a commonly encountered clinical condition and is most commonly secreted in excess by pituitary adenoma. The patient usually presents with galactorrhea and gonadal dysfunction. It is important to measure prolactin levels in all patients with unexplained primary or secondary amenorrhea. This was emphasized in some previous studies that showed that as many as 20% of patients with hyperprolactinemia did not have galactorrhea nor any signs of pituitary dysfunction. Vilar et al. reported on 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists. [1] Vilar et al. found that 56.2% of patients had prolactinomas, 14.5% had drug induced hyperprolactinemia, 9.3% had macroprolactinemia, 6.6% had non functioning pituitary adenomas, 6.3% had primary hypothyroidism, 3.6% had idiopathic hyperprolactinemia, and 3.2% had acromegaly. [1] In men, the diagnosis of prolactin secreting tumors is usually delayed until visual impairment or hypopituitarism appears. The reason is the male’s initial signs of gonadal dysfunction. These signs, decreased libido and occasionally galactorrhea, are associated with prolactin excess are usually ignored. There are many conditions associated with hyperprolactinemia. The most common causes are pregnancy, hypotalamo-pituitary disorders, drugs, and primary hypothyroidism. With the development of the third generation TSH assay and the inclusion of thyroid function testing in annual blood screenings, hyperprolactinemia caused by primary hypothyroidism become less common. Primary hypothyroidism can be associated with diffuse pituitary enlargement, which reverses with appropriate thyroid hormone replacement therapy. However, primary hypothyroidism associated [2,3] with a pituitary adenoma is extremely rare. Here, we report one such case. Case Presentation A 28-year-old female presented at her gynecologist’s office with 7 months of amenorrhea in 2009. The patient initially complained also of occasional dizziness, but she did not have headaches, visual disturbances, or galactorrhea. The patient also denied diarrhea or constipation, as well as dry skin, hot and cold intolerance, weight change, and muscle cramps. She never had menstrual abnormalities prior to this episode. She had recently married. Her only medical history was knee surgery 10 years before. Her family history was positive for thyroid cancer, which her sister had. She never smoked or abused alcohol and was exercising regularly. The initial laboratory work done by her gynecologist was negative for pregnancy, but it showed a prolactin level of 139 ng/mL. An MRI of the brain showed a 1.7 cm pituitary macro adenoma. The adenoma extended into the suprasellar region with indentation of the optic chiasm. Thyroid studies were also ordered but the patient did not follow up for reevaluation. The gynecologist started the patient on 0.25 mg of cabergoline twice weekly. After 6 months, the patient came back with the same complaint of amenorrhea and a new symptom of “feeling cold all the time.” Her prolactin level had decreased to 11.7 ng/mL and an MRI of the brain showed no change in the size of the pituitary adenoma. The patient was referred to an endocrinologist for possible surgery because of failure of the adenoma to shrink. Although no symptoms suggested hypothyroidism except cold intolerance, blood tests showed a TSH of 562.5 μU/mL, a FT4 of 0.18 ng/dL, and a reference range IGF-1 level. Cabergoline was discontinued and the patient was started on levothyroxine. The dosage was titrated to 112 μg daily. The patient was closely followed afterwards and 6 months later, her prolactin level was 23.2 ng/mL and her periods were regular; TSH had decreased to 340.237 μU/mL, her total T3 was 127 ng/dL, and her FT4 was 1.63 ng/dL. An MRI one year after she had started levothyroxine showed complete resolution of the pituitary adenoma. Discussion The hyperprolactinemia of hypothyroidism is related to several mechanisms. In response to the hypothyroid state, a compensatory increase in the discharge of TRH results in an increased stimulation of pituitary prolactin secretion. Hypothalamic thyrotropin releasing hormone (TRH) is a potent prolactin releasing factor, and it can cause thyrotroph hyperplasia. The high level of TRH in severe primary hypothyroidism and the lack of T4 feedback from the thyroid gland might cause proliferation and hypertrophy of both the pituitary gland’s thyrotrophs and lactotrophs. The hypertrophy may mimic a pituitary adenoma. With proliferation of the thyrotrophs and lactotrophs in primary hypothyroidism, as illustrated in our case, there is a significant increase in TSH levels and only a moderate increase in the prolactin level. In our patient, regression of her pituitary macroadenoma after treatment with levothyroxine confirmed the hypothesis of pituitary hyperplasia secondary to primary hypothyroidism. Cabergoline decreased her prolactin levels, but it did not decrease the size of the adenoma. This observation also supports the diagnosis of pituitary macroadenoma that was likely secondary to hypothyroidism. Furthermore, prolactin elimination from the systemic circulation is reduced in severe hypothyroidism; this contributes to increased circulating prolactin concentrations. Primary hypothyroidism can be associated with diffuse pituitary enlargement, which will reverse with appropriate thyroid hormone replacement therapy. In our case, primary hypothyroidism was not investigated and treated at the beginning of her care for three reasons: (1) the patient was relatively asymptomatic, (2) presented with a pituitary macroadenoma rather than a diffuse enlargement, and (3) was non-compliant. This case illustrates the importance of doing thyroid function tests in patients with hyperprolactinemia and pituitary macro adenoma. Doing so can avoid unnecessary pituitary surgery. However, surgical resection of a pituitary adenoma in primary hypothyroidism might still be necessary. In rare cases, for example, paradoxical pressure symptoms and development of a visual field defect will occur in the first months of thyroid replacement therapy. These symptoms suggest that monitoring for pressure symptoms during the treatment is important .[9] TSH secreting pituitary tumors caused by primary hypothyroidism should be distinguished from true thyrotroph neoplasia that results in secondary hyperthyroidism. The appropriate therapeutic approach is completely different. TSH-omas are usually invasive macroadenomas and are known to be difficult to treat. [6] The timeline of growth and regression of pituitary adenomas in hypothyroidism after replacement therapy has been started has not been clearly established. Studies show that discontinuation of T4 replacement in preparation for 131I therapy for only 3 weeks can cause significant enlargement of the pituitary gland. [2] In one reported case, the patient had rapid regression of a pituitary adenoma after one week of T4 replacement. In our case, the exact time course could not be [7] established. However, regression of the pituitary macroadenoma after treatment with levothyroxine confirmed the hypothesis of pituitary hyperplasia secondary to primary hypothyroidism. Conclusion Patients with hypothyroidism do not always present with typical symptoms. Our case illustrates that primary hypothyroidism can present in amenorrhea and pituitary mass. This suggests the importance of thyroid function testing during the investigation of hyperprolactinemia and pituitary adenoma in order to avoid unnecessary surgery. References 1. Vilar, L., Freitas, M .C., Naves, L.A., at el.: Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients. J. Endocrinol. Invest., 31(5): 436-44, 2008. 2. Passeri, E. and Tufano, A.: Large pituitary hyperplasia in severe primary hypothyroidism. J. Clin. Endocrinol.Metab., 96: 22-23, 2011. 3. Alves, C. and Alves, A.C.: Primary hypothyroidism in a child simulating a prolactin secreting adenoma. Childs Nervous System, 24(12): 1505-8, 2008. 4. Shimono, T, et al.: Rapid progression of pituitary hyperplasia in humans with hypothyroidism: demonstration with MR imaging. Radiology, 213: 383-388, 1999. 5. Beck-Peccoz, P. and Persany, L.: Tyrotropinomas. Endocrinology and Metab. ClinicNorthAmer., 37: 123-134, 2008. 6. Beck-Peccoz, P., Brucker-Davis, F., Persani, L., et al.: Thyrotropin-secreting pituitary tumors. Endocrine Rev.,17(6): 610, 1996. 7. Sarlis, N.J., Brucker-Davis, F., Doppman, J.L., et al.: MRI-demonstrable regression of a Pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy.J. Clin. Endocrinol. Metab., 82(3): 808-818, 1997. 8. Klibanski,A.:Prolactinomas.N.Engl.J.Med., 362: 1219-1226, 2010. 9. Stockigt, J.R., Essex, W.B., West, R.H., et al.: Visual failure during replacement therapy in primary hypothyroidism with pituitary enlargement.J. Clin. Enocr. Metabol., 43(5): 1094-1100, 1976. 10. Wajchenberg, B.L., Tsanaclis, A.M., and Marino Júnior, R.: TSH-containing pituitary adenoma associated with primary hypothyroidism manifested by amenorrhoea and galactorrhoea.Acta Endocrinologica, 106(1): 61-66, 1984.

Written by Dr. John Lowe, MA, DC and The Thyroid Patient Advocacy UK 1. What triggers hypothyroidism, is it genetic etc and why do we get and have thyroid problems? We have two classes of thyroid hormone disorders that lead to the need for people to take thyroid hormone. One disorder is hypothyroidism, or a thyroid hormone deficiency. The other is partial cellular resistance to thyroid hormone. In this latter disorder, cells respond only sluggishly to normal amounts of thyroid hormone. The two disorders have different causes. Iodine deficiency was once thought to be the most common cause of deficiency production of thyroid hormone by the thyroid gland. In geographical regions where there is too little iodine, iodine deficiency may still be the most common trigger. However, in areas where iodine is plentiful, autoimmune thyroid disease is the most common cause of hypothyroidism. But iodine deficiency and autoimmune disease are far from the only causes of hypothyroidism. Many people develop thyroid hormone deficiencies because of infections of the thyroid gland, thiocyanide in cigarette smoke, trauma to the gland as in whiplash injuries, and radiation exposure. Were subjected to a lot of x-rays, as when we travel inside airliners. Im convinced that going through screening x-ray fields in airports will increase the incidence of hypothyroidism. I've talked to too many x-ray researchers to trust our governments reassurances that those x-ray fields are virtually harmless. Other people are hypothyroid because of damage of the pituitary gland or hypothalamus. Pituitary damage can result from interference with the nerve supply to the gland from the upper cervical spine in the neck. And a wide array of chemicals can cause mutations in cells of the pituitary and hypothalamus. The hypothalamus and pituitary secrete hormones that regulate the thyroid gland. These are, respectively, TRH and TSH. When too little of one or both of these hormones is produced, or if they are mutated, then the thyroid gland doesnt produce enough thyroid hormone. We're not as sure about the various causes of partial cellular resistance to thyroid hormone. In the form of resistance called peripheral, the pituitary gland isn't resistant. Because of that, the people have in-range TSH and thyroid hormone levels. Nonetheless, they have symptoms characteristic of hypothyroidism. In the late 1990s, a member of my research and treatment team, Richard L. Garrison, MD, designated resistance type 2 hypothyroidism. In 2000, I published this in my book The Metabolic Treatment of Fibromyalgia. Several years later, Mark Starr, MD published a book titled Hypothyroidism Type 2: The Epidemic. I think the term helps some people understand thyroid hormone resistance. Dr. Garrisons reason for inventing the term was that resistance is somewhat analogous to type 2 diabetes. But I still use the traditionally term thyroid hormone resistance. People with resistance have hypothyroid-like symptoms because of one or more glitches in the persons cellular use of thyroid hormone. Most of them can recover, but they have to use fairly high doses of T3. The high doses override the resistance. As a result, cell function and metabolism become normal and the symptoms are relieved. The first unequivocally proven cause of thyroid hormone resistance was mutations in the c-erbA-beta gene on chromosome 3. This gene codes for the beta-thyroid hormone receptor. This is the main receptor by which thyroid hormone regulates the function of the cell. When the gene has a mutation, it causes one amino acid in the receptor, which is a protein, to be substituted by another amino acid. This causes the receptor to have a low affinity for thyroid hormone; the hormone doesn't readily bind to the receptor. More than a hundred mutations have been identified in the gene. These can be caused by radiation, some chemicals in cigarette smoke, and many of the vast array of chlorinated chemical contaminants that industry saturated us with during the 20th and 21st centuries. 2. Did Dr Lowe suffer cognitive problems as a child? Yes, I suffered from severe cognitive dysfunction. I especially remember how tough it was to comprehend when I read. If a sentence had, say, ten words, by the time I reached the last five words, I'd forgotten what the first five words were. I'd have to read the sentence over-and-over again. Eventually I might grasp what the meaning of the sentence was. It seemed to me that when I tried to hold the meaning in my mind, holes would spontaneously appear and some of the meaning would evaporate from my mind. Then I had to read the sentence again, may be several times. I struggled with this from elementary school through college. In school, I was passed by what was known as social promotion. This meant that I had failing grades, but for social reasons, they passed me anyway. I sneaked into the back door of junior college. You could do this in Florida by signing up for nighttime classes. For some reason, if one did this, he or she didnt have to go through the application process that would've caused a refusal of admission to the college. I learned some memory techniques. With those, I could at least scratch my way through most courses. I failed others more than once, such as English. Fortunately, I'd become an extremely good and showy drummer in popular local bands, such as the Laymen, and this brought me intelligent lady friends. They kindly taught me some study methods, and they tutored me in English grammar and other subjects. They also got me to study junior high and high school books. This enabled me to catch up on my huge educational deficits. So through their generous help, I compensated for a mind that still had spontaneously forming holes like Swiss cheese. I compensated well enough to move along through college. A turning point was toward the end of junior college. That was when I discovered Adelle Davis books on nutrition and began taking mega doses of nutritional supplements. This didn't cure my cognitive dysfunction, but it improved it enough so that I did better in college. When I transferred to the University of West Florida, I also sort of sneaked in. Because of my poor grades in junior college, they weren't going to allow me in. But then it was discovered that my father died in the Air Force, and because of some strange provision, that qualified me to be accepted. I didn't acquire what I consider normal cognitive function until I learned that I was thyroid hormone resistant. That was when I began taking Cytomel in my late thirties. Afterward, I didn't have to compensate for poor mental function, but my compensatory methods (such as memory techniques) had become habit by then. I still use them. With a normally functioning brain, if I'm going to give a presentation at a conference, I use those memory techniques so that I dont have to use notes during my presentations. 3. Was Dr. Lowes condition caused by Hashimoto? No, I never had anti-thyroid antibodies. I also had reference range TSH and thyroid hormone levels. Even my TRH-stimulation test results were in range. 4. Does your current dose of T3 fluctuate? Mine doesn't very often nowadays. In years passed, I occasionally felt like I should slightly decrease my usual 150 mcg of T3. At other times, I felt I should increase it slightly. I typically decreased or increased it by 12.5 mcg. However, years ago, the new instruments called indirect calorimeters became available for measuring the basal metabolic rate (BMR). Since I began using these instruments, if I feel I need to alter my dose, I measure my basal metabolic rate. I also run an ECG/EKG and measure the voltage of my hearts R waves. When I see that my BMR is exactly where it's supposed to be, and my R-wave voltage is where it's supposed to be, I leave my T3 dose where it is. I wait, and usually within a few days, I've lost the feeling that I need to decrease or increase my dose. This has kept me from altering my dosage very often. I rarely do, and only briefly, in the course of a couple of years. I think my feeling that I need to alter my dosage was usually due to some other factor, such as insufficient sleep, allergy-induced fatigue, or a phase in my chronobiology. The term chronobiology refers to the biological and psychological cycles of living organisms as they adapt to the rhythms of the sun and moon. The cycles are probably a source of much confusion over whether one is on the right dose of thyroid hormone, or the right product for the individual. Its important to consider that a phase of your chronobiological cycles may account for your feeling that you need more or less thyroid hormone. Sometimes it's best just to wait and see whether the perception changes over time. 5. How useful is a reverse T3 test in diagnosing hypoyhyroidism? I believe the test is of virtually no value in diagnosing hypothyroidism, if by hypothyroidism we mean a thyroid hormone deficiency. When the thyroid gland produces too little T4 and T3, less of these two hormones are available. The vast bulk of what the thyroid gland produces and releases into the blood is T4. With a lower-than-usual amount of T4 available, it's likely that more of it will be converted to T3 rather than reverse T3. This presumably results from a need to keep the T3 high enough to maintain effective cell function. Also presumably, reverse T3 production from T4 will decrease to some degree. As a result, in moderate-to-severe hypothyroidism we might find low T4, low-to-mid-range T3, and a low reverse T3. However, as far as I know, no researchers have shown that this lab result pattern is useful for diagnosing hypothyroidism. This pattern in hypothyroidism is only a conception based on principles. But in actual practice, I've rarely seen this pattern in hypothyroid patients. I believe the reason is that when the TSH and thyroid hormone levels are in range, their levels vary (as Japanese researchers say) dramatically every thirty minutes or so. There is no correlation from thirty-minute period to thirty-minute period, day-to-day, and week-to-week. In my opinion, the reverse T3 has served us best in diagnosing a condition that has a variety of names: euthyroid sick syndrome, low T3 syndrome, and non-thyroidal illness syndrome. The word euthyroid, of course, means that the person has in-range TSH, T4, and T3 levels. In this condition, the hypothalamus secretes less TRH, the pituitary secretes less TSH, and less thyroid hormone is transported into cells. Also, the enzyme called 5-prime deiodinase, which converts T4 to T3, becomes far less active. Another enzyme, 5 deiodinase (no prime as a modifier) becomes more active and converts more T4 to reverse T3. The words sick syndrome is somewhat misleading. That term is used presumably because the condition was first identified in sick people, such as anorexics and hospitalized patients in critical condition. Studies showed that the patients had steeply raised cortisol levels. It's their high cortisol levels that inhibit the enzyme (5-prime deiodinase) that converts T4 to T3. I've found no evidence that this condition becomes chronic, as Dr. Dennis Wilson proposed. Instead, the research literature shows that within a week or two, TSH secretion increases and 5-prime deiodinase escapes the inhibition by cortisol. This happens even though the persons cortisol levels remain high. For example, if the person undergoes prolonged treatment with prednisone, within a week or two, the TSH level returns to its previous level and 5-prime deiodinase becomes normally active again. Old studies show that on average, most people convert more than 50% of their T4 to reverse T3; correspondingly, they convert less than 50% of T4 to the metabolically active hormone T3. And the levels of reverse T3 fluctuate up and down through the day. Because of this, I'm never confident of coming to a conclusion that someone has a problem with high reverse T3, not unless the person has had multiple measures of the reverse T3 over a 24-hour period. Like the TSH, free T4, free T3, reverse T3 levels vary dramatically every 30 minutes or so. Depending on when a persons blood is drawn or saliva taken. Sometimes the levels will vary enough so that a clinician will give the patient a different diagnosis from the one that he or she would have given 30-minutes before or after the blood or saliva sample was taken. So blood levels vary rapidly. Because of this, I don't believe the reverse T3 or the other lab tests in general are very useful. However, I do believe the reverse T3 is useful under one circumstance: when we have enough measures to get averages over time, and when the levels are regularly way out of range. So, in my view, the reverse T3 can be useful, but I think it's usefulness is limited, which is true of the TSH and other thyroid hormone levels. 6. What is thyroid resistance and how is it treated? "I cannot tolerate T4 or natural dessicated thyroid, only cytomel, but my doctor doesn't know how much T3 to give me. I dont seem to get hyperthyroid at all with 100 mcg, but it seems like a lot. Im a 62 yr old female, 140#. I have been diagnosed with low voltage, by a cardiologist, but never knew until hearing you tonight that this was connected. People say too much T3 will cause heart problems. I would like to hear what you have to say on this thanks!" Unless a person takes a daily dose of T3 that is too high for him or her, then it's highly unlikely that the T3 will cause any heart problems. The same is true, however, of T4. Keep in mind that T4 is not a hormone; its a prohormone and is metabolically inert until its converted to T3. So, if it were true that taking too much T3 causes heart problems, the same would be true of taking too much T4, it that some of it will be converted to T3. The only person for whom a small dose of T3 would be harmful would be someone with an extremely fragile heart. Among ambulatory people, this is extremely rare. When a person begins to take an effective dose of T3, his or her previously understimulated heart beats more forcibly. The person isn't used to feeling the vibrations produced by the more forceful projection of blood out of the left large heart chamber (ventricle) against the inner wall of the aorta. Because of this, the person perceives the pounding. Many people misinterpret the pounding as overstimulation of the heart. In fact, it's just a normal occurrence, as in people who havent been hypothyroid. Perception of the pounding is usually enhanced if the person lies on a bed. The bed acts as a sounding board, and this amplifies the perception of pounding and may frighten the person. But if the person understands that the pounding is a harmless phenomenon, he or she will become desensitized to it after a week or two. The pounding from vibrations continue, but the person then isn't aware of it. Of course, if the heart beats too rapidly, say more than 90-to-100 beats per minute at rest, there are possible explanations other than too much T3. If the persons dose is below, say, 90-to-100 mcg per day, chances are the problem is something related to over-activity of the sympathetic nervous system. Low or high blood sugar is a common cause of the over-activity. B complex vitamin deficiencies, such as a B1 and B12, may also be the cause of the rapid heart rate. When such other factors are interacting with T3 to cause a rapid heart rate, the proper way to relieve the problem isn't to stop the T3 altogether. It's proper to reduce the dose low enough to relieve the rapid heart rate, and then identify and correct the other problem. Then the person should be able to use a dose of T3 high enough to be fully effective without causing the heart to beat too fast. Incidentally, before the TSH scourge came to afflict patients some forty years ago, the Physicians Desk Reference specified what a full replacement dose of T3 was for a person who has no thyroid gland. The dosage range was 75-to-100 mcg. So your 100 mcg wouldnt necessarily be considered too high. Dosing is always highly individual, though. Because of that, the question to ask is whether that amount is too high, just enough, or too little for you as an individual. In your question you wrote, "People say too much T3 will cause heart problems". I would rephrase the statement to read, Too much T3 for a particular individual may cause heart problems. I've seen many patients who were thyrotoxic from T4 alone, T4/T3 products, and T3 alone who had no adverse heart effects. It's safest, of course, to avoid anything more than mild and brief overstimulation by thyroid hormone, although the endocrinology specialty has grossly exaggerated the potential for harm. 7. Do you have an article about T3 that you can link us to? At the link below is my reply to a physician who claimed that no one should take T3 and that its dangerous. I hope my reply to him is helpful: http://www.drlowe.com/jcl/comentry/t3dangerous.htm

Written by Camille Noe Pagán If you have thyroid disease, you’re more prone to have high cholesterol levels. Though high cholesterol can be caused by an unhealthy diet and genetic factors, certain medical factors can play a role, too. In fact, as many as 13% of people who have hypothyroidism (underactive thyroid) will also have high levels of “bad” LDL cholesterol. Hypothyroidism is also linked with too-high levels of triglycerides (blood fats that are associated with cholesterol). Both of those issues increase your risk for heart disease and stroke. Hyperthyroidism (overactive thyroid) isn’t as common as hypothyroidism. It may cause low levels of “good” HDL cholesterol. If you’re diagnosed with hyperthyroidism, your doctor will monitor your cholesterol levels to make sure you stay healthy. If you have thyroid disease, high cholesterol levels, or both, here’s what you should know. What’s the Link? Cholesterol is a waxy substance that circulates in your blood. Your body makes it, and it’s also found in animal foods. There are a couple different types of cholesterol: High-density-lipoprotein (HDL) cholesterol, or “good” cholesterol. Low levels of HDL cholesterol can contribute to heart disease and other issues, especially if your LDL cholesterol and triglyceride levels are high. Low-density-lipoprotein (LDL) cholesterol, or “bad” cholesterol. When your LDL cholesterol levels are too high, your arteries can become too narrow and get blocked. That can cause stroke and heart problems. Triglycerides are fats from the food you eat that circulate in your body, which can be stored in fat cells. Triglycerides aren’t actually a type of cholesterol, but their levels are measured along with HDL and LDL in order to determine your odds of developing heart conditions. Your thyroid is a butterfly-shaped gland in your neck. It produces hormones that help regulate your body’s metabolism. When you have hypothyroidism, your body doesn’t make enough thyroid hormones. This can increase your cholesterol levels. In fact, research suggests that even slightly low levels of thyroid hormones can cause a spike in cholesterol. Thyroid hormones help your liver process blood. When your thyroid hormone levels are low, your liver processes blood more slowly, which can lead to higher levels of cholesterol in your bloodstream. That can cause a buildup of cholesterol in your arteries. Treating High Cholesterol and Thyroid Disease The good news is, treating thyroid disease may improve your cholesterol levels. Doctors treat hypothyroidism with thyroid replacement hormone medications. There’s no cure for hypothyroidism. That’s why improving your cholesterol levels doesn’t improve your thyroid hormone levels. Experts recommend that adults who’ve been diagnosed with high cholesterol levels get tested for an underactive thyroid. If you’re being treated for an underactive thyroid, your doctor will monitor your cholesterol levels. Some people with hypothyroidism may not lower their cholesterol levels enough with thyroid replacement hormones. If that happens to you, your doctor may recommend you take other measures, such as eating healthier, exercising regularly, and taking a cholesterol-lowering medication. SOURCES: JAMA Internal Medicine, 2014: “Thyroid Function Testing in Patients with Newly Diagnosed Hyperlipidemia.” UpToDate: “Lipid abnormalities in thyroid disease.” Mayo Clinic: “High cholesterol.” Pharmacy Times: “Thyroid Problems and Cholesterol are Connected.” American Heart Association: “Cholesterol and Diabetes.” Cleveland Clinic: “Triglycerides and Heart Health.” Endocrine Practice: “American Association of Clinical Endocrinologists And American College Of Endocrinology Position Statement On Thyroid Dysfunction Case Finding.” The Journal of Clinical Endocrinology and Metabolism: “Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones.” The Open Cardiovascular Medicine Journal: “Effects of Thyroid Dysfunction on Lipid Profile.” American Thyroid Association: “Hypothyroidism (Underactive).” Clinical Thyroidology for the Public: “Patients with hypothyroidism adequately treated with levothyroxine have higher levels of cholesterol compared to healthy controls.”

Written by Henry H. Lindner MD, www.hormonerestoration.com About the Clinical Diagnosis and Treatment of Hypothyroidism Current professional guidelines for the diagnosis and treatment of hypothyroidism abandon clinical medicine for a laboratory exercise: TSH and free T4 normalization. This approach is both illogical and ineffective. The TSH level is not a measure of thyroid hormone sufficiency in any given patient, either untreated or treated; reliance on the TSH produces both under- and over-diagnosis and undertreatment. Dysfunctional central hypothyroidism with a normal TSH may be more common than primary hypothyroidism, and TSH-normalizing T4 therapy neither normalizes T3 levels nor restores euthyroidism. The TSH test is useful only for investigating the cause of clinically-diagnosed hypothyroidism. The free T4 and free T3 levels are more direct indicators of thyroid sufficiency, but their reference ranges have inappropriately low lower limits due to laboratories’ inclusion of unscreened persons and hypothyroid patients in their samples. A normal free T4 does not imply thyroid sufficiency. The diagnosis and treatment of hypothyroidism must clinical, guided by signs and symptoms first and by the free T4 and free T3 levels second. Every symptomatic patient with relatively low free T4 and/or free T3 levels deserves a trial of T4/T3 combination therapy titrated to obtain the best clinical response. The ultimate test of whether a patient is experiencing the effects of too much or too little thyroid hormone is not the measurement of hormone concentration in the blood but the effect of thyroid hormones on the peripheral tissues(1, 2). 1. Official TSH-T4 Reference Range Thyroidology The active thyroid hormone, T3, is one of the most powerful molecules in the human body, affecting every system, every tissue of the body and every aspect of our well-being and health. It increases the mitochondrial energy production (2, 3) thereby improving the function of every tissue and organ in the human body. It has other direct and indirect effects that we are only beginning to understand. The symptoms and signs of hypothyroidism are many and various. Hypothyroid patients may receive many different diagnoses.(4) (See Table 1.) Even mild hypothyroidism degrades a person’s quality of life and long-term health; therefore its diagnosis and effective treatment is essential to the practice of medicine. What guidance do physicians now receive? Table 1. Signs and Symptoms of Hypothyroidism Fatigue, excessive need for sleep Cold intolerance Weight gain, cannot lose weight Constipation, poor digestion Muscle or joint aches, stiffness Myxedema in face, lower legs Cognitive dysfunction Dry skin, itching Headaches Depression or anxiety Elevated total and LDL cholesterol Atherosclerosis Hypertension Carotenemia, yellowing of skin Dry hair, hair loss Slow heart rate, palpitations Insomnia, restlessness Heavy menses or amenorrhea Infertility Allergies The American Association of Clinical Endocrinology (AACE) and American Thyroid Association (ATA) 2012 practice guidelines endorse the TSH test as the best screening test for the diagnosis of primary hypothyroidism and the best guide for its treatment.(5) The guidelines assume that almost all hypothyroidism is primary; that central hypothyroidism is rare and confined to persons with obvious hypothalamic-pituitary (HP) damage or disease. The guidelines thus assume that an anatomically-intact HP system always function perfectly to maintain optimal thyroid levels and effects. No supporting evidence or argument is offered for any of these assumptions. Regarding the actual thyroid hormone levels, the guidelines state that the free T4 (FT4) should be checked only if central hypothyroidism is suspected, and testing for free T3 (FT3) is of no value.(6) The signs and symptoms of hypothyroidism are briefly mentioned, but the guidlelines assert that clinical rating scales have been superseded by sensitive serum testing; that the physican should rely on test results and their reference ranges. Even though the guidelines rely on the TSH for screening and for treatment, they admit that the diagnosis of hypothyroidism rests on a low FT4. Here again, no evidence or argument is offered for this use of any laboratory’s FT4 range as a diagnostic range. The production and meaning of laboratory reference ranges is not even discussed. (See below.) The guidelines leave the diagnosis of hypothyroidism in the hands of laboratory scientists. The goal of treatment of primary hypothyroidism is said to be a normal TSH. Again, no evidence or argument is provided to support the claim that normalizing the TSH restores euthyroidism in all or most patients. The evidence actually falsifies this claim. (See below.) During treatment the physician is told to ignore the “clinical criteria”—the patient’s signs and symptoms. Both the thyroid hormone levels and clinical criteria are said to lack “sufficient specificity to serve as therapeutic endpoints”.(7) The latter assertion is neither explained nor supported. The guidelines mention that normalizing the TSH with T4 therapy may leave the FT3 low-normal or low; but the physician should not be concerned with this deficiency of the active thyroid hormone. The guidelines warn physicians not to treat any patient, no matter how symptomatic, unless the diagnosis is “biochemically confirmed”(8)—i.e. unless the TSH is above or the FT4 below the laboratory’s reference ranges. In sum, physicians are expected to accept this TSH-T4 reference range thyroidology on faith and to ignore their patients’ signs, symptoms and relative thyroid hormone levels. Thyroidology is reduced to TSH and FT4 reference range management. A patient with a normal TSH and free T4, anywhere from the bottom to the top if its range, is “euthyroid”, treated or untreated, regardless of signs or symptoms of hypothyroidism. Any persisting hypothyroid symptoms in a person whose TSH and/or FT4 are normal must have another cause: chronic fatigue syndrome, fibromyalgia, depression, poor habits, obesity, etc. There is disagreement about this paradigm even among professional bodies. The National Association of Clinical Biochemists (NACB) guidelines recognize that merely normalizing the TSH in primary hypothyroidism results in undertreatment. They advise that T4 therapy should reduce the TSH to below 2.0mIU/L and raise the FT4 into the upper third of its reference range.(9) The consensus statement by the Royal College of Physicians advises that the appropriate dose of levothyroxine is that which “restores the euthyroid state and relieves symptoms…” and that in most patients these goals will be achieved “by a dose of thyroxine resulting in a normal or slightly raised serum thyroxine concentration, a normal serum triiodothyronine concentration, and a normal or below normal serum thyroid T4 stimulating hormone.”(10) A senior thyroidologist in the UK has written, “Some patients achieve a sense of wellbeing only if free T4 is slightly elevated and TSH low or undetectable. The evidence that this exogenous form of subclinical hyperthyroidism is harmful is lacking… and it is not unreasonable to allow these patients to take a higher dose if T3 is unequivocally normal.”(11) In contrast, the authors of the UpToDate article(12) on the treatment of hypothyroidism imply that a low TSH during T4 treatment is “subclinical hyperthyroidism” with the same implications as the endogenous form. No evidence is provided to support this claim, and there is much evidence that falsifies it. (See Sect. 5.) Regarding secondary/central hypothyroidism, The Williams Textbook of Endocrinology acknowledges that in such cases the TSH is usually normal and FT4 often low-normal(13), i.e. the diagnosis often is not “biochemically confirmed”. I will show that that TSH-T4 reference range thyroidology is illogical and ineffective, resulting in both under- and over-diagnosis and in an almost universal undertreatment of hypothyroidism. Since it began to be adopted in the 1970s, there has been an explosion in the number of people diagnosed with chronic fatigue syndrome, fibromyalgia and depression. While their causes are multifactorial, each of these disorders shares many symptoms with hypothyroidism and should be considered as due to hypothyroidism until proven otherwise. 2. The Illogicality of TSH-based Thyroidology The guidelines promote the TSH test for screening and for treatment, yet defer to the FT4 to confirm both the diagnosis and treatment. So why attempt to rely on the TSH at all? In order for TSH-based thyroidology to work, all its unstated assumptions would have to be true: The process of TSH secretion is always perfect unless there is known damage or disease affecting the HP system. Almost all hypothyroidism is primary. The TSH level is a reliable inverse measure of thyroid levels and effects throughout the body, so a normal TSH assures thyroid sufficiency for almost all persons. TSH secretion reacts to once-daily oral levothyroxine therapy exactly as it does to endogenous thyroid secretion, so normalizing the TSH always restores thyroid sufficiency. It is with good reason that these assumptions are never stated: they are illogical, unphysiological, and/or falsified by scientific studies and the daily reality of clinical practice. The first and fatal problem with TSH thyroidology is its illogicality. The level of a pituitary stimulating hormone is not a reliable measure of hormone levels or end-organ effects. Indeed, in no other case do we try to use a pituitary hormone as a surrogate inverse measure of hormone levels or effects. We do not use luteinizing hormone (LH), follicle-stimulating hormone, or adrenocorticotropin levels to diagnose or to treat gonadal or adrenal hormone deficiencies. Dysfunctional LH production is the most common cause of male hypogonadism, and LH is typically suppressed with therapy. We hormone deficiencies by symptoms, signs, and free hormone levels. We then check the level of the pituitary hormone level to find the cause of the hormone deficiency. A high pituitary hormone level implies that the primary gland is dysfunctional; a normal or low level implies that the HP system itself is dysfunctional. Thyroidology should be no different. Using the TSH as a surrogate measure of T3 effect in a given patient is as illogical as insisting that one’s home-heating thermostat is working perfectly even as one’s house is getting colder and colder. Even if the TSH is elevated, it is a compensatory mechanism. The increased stimulation of the dysfunctional thyroid gland may indeed work to maintain thyroid levels and effects. It is true, as with other pituitary stimulating hormones, that there is a correlation between TSH and FT4 levels due to the presence of primary hyper- and hypothyroidism in the population. However, this correlation does not imply that the TSH level is a reliable inverse measure of thyroid hormone levels or effects in any given patient, particularly when it is in or near its reference range. The reliance on the TSH is also inconsistent with what we know about the complexity and fallibility of the entire system of HP function, thyroid gland function, T4-to-T3 conversion, and T3-effector mechanisms. Dysfunction can occur at any level. The HP system itself is extremely complex, certainly far more complex than the thyroid gland and therefore much more likely to be dysfunctional. It is part of the brain and is affected by inputs from many regions of the brain and by many neurotransmitters, environmental chemicals, drugs, illnesses(14), stress, and other factors. All its proteins are subject to genetic mutation. Indeed, a number of mutations and other molecular disorders including the secretion of an inactive form of TSH have been associated with dysfunctional central hypothyroidism(15,16,17). Like LH and growth hormone, TSH production declines with age. The TSH response to response to low FT4 levels declines by 80% between ages of 20 and 80(18). Even if we had some independent way of knowing that HP function was perfect in a given patient, the TSH level still would tell us only about the response of the HP system to circulating T4 and T3, not about T3-effects in other tissues of the body. The HP system differs from other tissues; it more sensitive to circulating T4. The brain and pituitary gland have higher levels of the deiodinase D2 compared to other tissues, so they convert T4 to T3 more avidly(19, 20). The central nervous system has no D1, but many other tissues in the body do and D1 is a major determinant of T3 production in the body. The production and activity of D1, D2, and D3 are variously affected by many factors(21). There are also four different thyroid hormone receptors(22, 23) and at least ten different active transport systems with variable tissue distribution(24, 25, 26). All of these proteins are subject to single nucleotide polymorphisms(27, 28) that can affect TSH secretion, the response of the thyroid gland to TSH, T4-to-T3 conversion and action of T3 in various tissues. Local factors ultimately determine tissue and cellular thyroid levels and effects. Peripheral thyroid hormone resistance may be more common than realized(29). To reduce all of thyroidology to TSH or even T4 management is to ignore both the known and unknown complexities of the endocrine system. Case reports of various diseases and damage to the HP system are interesting, but do not imply that all central hypothyroidism (CH) is associated with abnormal imaging studies. There are many reports of persons with CH whose imaging studies are normal(30, 31, 32), and I see such patients frequently. They have a dysfunctional central hypothyroidism, usually of hypothalamic origin. Normal aging blunts the TSH response to TRH(33), and 2.5% of the elderly have a low FT4 index with an inappropriately normal TSH and no evidence of any HP abnormalities(34). I assert that a more sensitive clinical approach to case-finding using signs, symptoms, and meaningful FT4 and FT3 reference ranges, (Sect. 2.) will reveal that dysfunctional CH is much more common than primary hypothyroidism. Consider that even in cases of CH due to obvious damage or disease the TSH is usually normal and the FT4 frequently low-normal(35, 36). There are various degrees of CH in such cases. Logically, in less severe cases of dysfunctional CH, both the TSH and FT4 will usually be normal. Thus a patient who has hypothyroid symptoms, a normal TSH, and a low-normal or low FT4 and/or FT3, and whose symptoms resolve with thyroid optimization has CH by definition. Many cases of CH, and all cases of dysfunctional CH are undiagnosable with the AACE/ATA guidelines. This reliance on the TSH is supported by some specious arguments and rationalizations. The TSH is said to be the best test of thyroid sufficiency due to its sensitivity. The latest generation of the TSH test is indeed sensitive to lower TSH levels than could be measured by earlier tests. The TSH test is also sensitive in that it responds in a logarithmically-amplified degree to changes in serum FT4. However, neither of these facts implies that the TSH is the right test. This “Immaculate TSH” doctrine has corrupted all of thyroidology, including most clinical studies. Researchers routinely equate a normal TSH with euthyroidism, leading to ambiguous results and false interpretations. Consider the conflicting studies on “subclinical hypothyroidism” where the TSH is elevated but the FT4 and FT3 are normal. They can be anywhere from the bottom to the top of their ranges, with vastly different clinical implications. A high TSH with mid-range FT4 and FT3 levels and no symptoms is not hypothyroidism at all. On the contrary, if both FT4 and FT3 are low-normal the patient may be severely hypothyroid; even fall into a myxedema coma(37). The daily result of the AACE/ATA guidelines is that physicians can only diagnose “subclinical hypothyroidism” which is often not hypothyroidism, and primary hypothyroidism. They cannot diagnose dysfunctional central or mixed central/primary hypothyroidism where the TSH and FT4 are normal. They cannot even diagnose the majority of cases of CH caused by disease or damage of the HP system, until that pathology becomes evident in some other way. When they do diagnose hypothyroidism, they simply normalize the TSH in primary hypothyroidism and the FT4 in central hypothyroidism, practices that have been repeatedly shown to result in undertreatment. (See below.) The diagnosis and treatment of hormone deficiencies must instead proceed according to known physiological principles. We first determine that a hormone deficiency may exist based upon clinical criteria. This is first-rank evidence—of actual end-organ hormone effect. Then we search for less direct second-rank evidence, i.e., for rather low free hormone levels in the serum. If we diagnose a hormone deficiency, we then check the level of the pituitary stimulating hormone in order to determine the cause of the deficiency or excess(8). 3. The Problem with the FT4 and FT3 Reference Ranges In thyroidology, the reliance on the TSH has produced a unique problem with the reporting of the thyroid hormone levels. Laboratory reports create confusion first of all because they contain a mixture of physician-adjudicated diagnostic ranges and 95%-inclusive population ranges. The nature of the range is usually not indicated. Among the diagnostic ranges are fasting serum glucose, Hgb A1C, 25-OH Vitamin D and lipid panels. Physicians are beginning to think that all ranges are diagnostic. Endocrine reference ranges, however, are just population ranges. They are mere statistics that include 2 standard deviations from the mean—the middle 95%—almost all—of some group of “apparently healthy” adults. The subjects are usually laboratory employees and their friends and relatives. They are screened for medications and diseases, but not for symptoms of hormone deficiency. The limits represent the 2.5th and 97.5th percentile levels of this essentially unscreened group. Only those with levels below the 2.5th percentile are defined as “low”. In practice, this means that a physician will tell a symptomatic patient with hormone levels near the bottom of the range, say at the 5th percentile, that he/she has a sufficient hormone level when in fact 95% of unscreened adults have higher levels. Using a 95%-inclusive unscreened population reference range as a diagnostic range may work if one’s goal is only to detect overt disease or damage of the endocrine system, which are rare. It fails, however, to detect any level of hormone deficiency that affects more than 2.5% of that population. HP and glandular dysfunction are known to occur due to age-related deterioration of the endocrine system, chronic stress, unhealthy lifestyles, obesity, environmental toxins, genetic abnormalities, etc. It is highly likely that a population that is not screened for symptoms will contain more than 2.5% of persons with suboptimal hormone levels. For evidence of this one need only look at the breadth of the endocrine reference ranges. The lower and upper limits for many hormones differ by factors of 2 up to 5—surely these cannot represent sufficient, let alone optimal levels. One can double, triple or even quintuple a person’s low-normal hormone level and still be within the range. Such an intervention would produce remarkable changes in the person’s physiology. Individuals also vary greatly in their hormonal needs. In thyroidology, since we have no reliable test of T3 levels and effects within the tissues and cells of the body, the best laboratory indicators of thyroid status are the FT4 and FT3 (9) levels in the serum. Most physicians trust that these ranges are adjudicated or based upon carefully screened populations. However, the FT4 and FT3 reference ranges or not even 95%-inclusive unscreened population ranges; they are hypothyroid patient ranges, contaminated by the inclusion of physician-ordered TSH-normal test panels. How does this occur? Every commercial FT4 kit comes with a manufacturer’s suggested reference range. This range is usually based on the testing of 120 or more “apparently healthy” persons with screening for symptoms. Each laboratory using the kit has to produce its own reference range and has the option of either using the manufacturer’s range, the published literature, tests done on their own population, or some combination of these(38). Rather than identify, screen, and test 120 or more healthy persons to produce their FT4 and FT3 ranges, laboratories typically save time and money by adjusting the manufacturer’s reference range using their own physician-ordered thyroid panels in which the TSH was normal(39). They thus produce ranges that include untreated and treated hypothyroid patients. This is yet another way in which the immaculate TSH doctrine has corrupted thyroidology. The effect of this practice is again seen in the breadth of the ranges. Whereas studies of adult non-patients, without screening for symptoms, yield a 95%-inclusive FT4 range of around 1.0 to 1.6ng/dL (12.9–20.6pmol/L)(40, 41, 42, 43), most laboratories report much broader FT4 ranges, typically having lower limits of only 0.6 to 0.8ng/dL (7.7 to 10.3pmol/L) and upper limits of 1.8 to 2.2ng/dL (23.2 to 28.4pmol/L). The best explanation for these broader limits is that the lower limits are reduced by the inclusion of patients with untreated central/mixed hypothyroidism, and the upper limits raised by the inclusion of levothyroxine-treated primary hypothyroidism patients, who require higher FT4 levels to normalize their TSH. The results of this careless laboratory practice are devastating for hypothyroid patients. Many symptomatic persons have FT4 levels below 1.0ng/dL and normal TSHs, warranting a diagnosis of CH. They would be diagnosed with the use of a reasonable unscreened population range. However, if a range were produced using careful screening, if all persons with any signs or symptoms of hypothyroidism were excluded, including those with elevated cholesterol levels, the resultant FT4 lower limit would certainly be higher, probably around 1.2ng/dL (15.5pmol/L). One could also argue that the reference range should be based only on 25 to 35 year-old subjects, as the decline in hormone levels with aging is deleterious and not adaptive. However, even with a tighter FT4 reference range, the 10 clinician must still use clinical judgment since any reference range, no matter how tight, is just an arbitrary statistical treatment of some population. Persons differ in their need for thyroid hormone(44, 45), their conversion of T4 to T3, their sensitivity to T3, and in other mechanisms required for thyroid hormone action. The 5th or even 50th percentile may not be sufficient for some. 4. T3 and the Ineffectiveness of TSH-Normalizing T4 Therapy Once-daily oral thyroid hormone replacement is an unphysiological intervention in the functioning of a very complex system. In contradiction to the AACE/ATA guidelines, most studies of TSH-normalizing T4 therapy (TSHT4Rx) show that it does not restore clinical euthyroidism in most persons. Patients receiving TSHT4Rx continue to have signs and symptoms of hypothyroidism. They display significant impairment in psychological well being compared to controls of similar age and sex(46). They have decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls(47). They have poor performance on various domains of neurocognitive functioning, and levels of wellbeing significantly lower than those of the general population(48). They are twice as likely to be taking anti-depressant medications(49). They have persistent endothelial dysfunction(50), and an increased risk of cardiovascular morbidity(51). They have higher hypothyroid index scores and higher BMIs than euthyroid controls(52). They have 21% greater fat mass than controls(53). After thyroid ablation, patients on TSHT4Rx gain weight (avg. 4kg), whereas those who receive TSH-suppressive therapy do not(54). Patients on TSH-normalizing doses of either T4 or T4/T3 have much worse scores than euthyroid controls on various measures of mentation and mood(55). Women on T4 therapy have more depression and anxiety than women not taking T4, and their symptoms are worse with higher TSH levels within the range(56). The corrupting effect of TSH-based thyroidology is seen in studies of the treatment of subclinical hypothyroidism (SH) and their interpretation. When patients with SH do not benefit from low T4 doses that normalize the TSH, physicians conclude that SH produces no symptoms and should not be treated. For instance, in one study the SH patients had FT4 and FT3 levels only slightly lower in the ranges than healthy controls. When these patients were given low-dose T4, the TSH was normalized, but the FT3 levels did not rise compared to placebo. Since there was no improvement in cognitive function with treatment, the authors concluded that there is no cognitive impairment in SH.57 A better conclusion is that normalizing the TSH with low doses of T4 does not restore euthyroidism, and the failure to raise the T3 level is a useful marker of under-treatment. In another study, increasing the patients’ doses of T4 lowered their TSH from mid-range to low-normal but had no effect at all on their symptoms. The authors concluded that merely normalizing the TSH to any point within the range is sufficient(58). A better conclusion is that the TSHT4Rx is similarly ineffective at any TSH level within the range. Since neither a normal TSH nor FT4 guarantees euthyroidism, and since merely normalizing the TSH with T4 constitutes inadequate treatment in most patients, we must reinterpret every study and review that was based upon TSH-T4 reference range endocrinology. The use of the TSH to guide treatment was definitively tested in the late 1980’s. In the only rigorous study of clinically-guided T4 therapy, four experienced clinicians adjusted the T4 doses of 148 hypothyroid patients based on clinical criteria, using physical signs and symptoms as quantified with the Wayne index(59). For the patients they judged to be clinically euthyroid, the treated TSH reference range was <0.1-13.7mIU/L (conventional range: 0.35-5.0mIU/L). The treated FT4 range was nearly 50% higher than the conventional range (12-36pmol/L vs. 9-25pmol/L), and the treated FT3 range was virtually identical to the conventional range (3.0-8.6 vs. 2.9-8.9pmol/L). With T4 replacement therapy, TSH proved to be the least accurate measure of euthyroidism and FT3 the most accurate. The authors concluded that “biochemical tests of thyroid function are of little, if any, value clinically in patients receiving thyroxine replacement”. There has never been a comparable study that has contradicted the authors’ findings or conclusion. 5. Why TSH-Normalizing T4 Therapy does not Work As the above study suggests, the explanation for the inadequacy of TSHT4Rx is found in the T3 levels. The serum T3 level reflects the amount of T4-to-T3 conversion throughout the body and therefore the T3 levels in the tissues. Patients with untreated primary hypothyroidism (PH) are much less symptomatic if their FT3 is normal rather than low(60). TSHT4Rx produces lower T3 levels than in healthy controls(61, 62, 63, 64, 65, 66, 67). After thyroidectomy, with no thyroidal T3 production, the restoration of pre-operative T3 levels requires T4 doses that either suppress the TSH(68) or produce T4 levels 40% higher than before surgery(69). In patients with subclinical hypothyroidism, TSHT4Rx can actually lower 12 the T3 compared to pretreatment levels(70). On TSH-suppressive T4 therapy, a FT4 that is 66% higher than controls produces the same total T3 level and no symptoms of hyperthyroidism(71). T4-treated patients have the same 24-hour urine FT3 levels as untreated hypothyroid patients(72). Patients feel better when their TSH is suppressed below the range and their FT4 and FT3 are in the upper half of their ranges. The FT4 dose they require is 50mcg greater than that which normalizes their TSH response to thyrotropin-releasing hormone(73). The inability of TSHT4Rx to raise FT3 levels or produce clinical euthyroidism has led some investigators to recommend adjusting T4 therapy based upon the T3 level(74, 75). Why are T3 levels and effects so low in TSHT4Rx? First, there is no guarantee that the treated patient has perfectly vigorous TSH production to start with, in which case using the TSH to determine treatment must result in undertreatment. Aging is accompanied by a reduction in HP function, and middle-aged adults are the most frequent recipients of thyroid replacement and most often included in studies. A degree of HP dysfunction appears to be widespread—as indicated by the low lower limits seen in laboratory FT4 reference ranges that include TSH-normal symptomatic patients. In addition, the HP feedback control system evolved to interact with the thyroid gland and its continuous production of thyroid hormones, not to tell doctors how to prescribe unphysiological once-daily oral T4 therapy. The brain and pituitary have high levels of D2 and convert T4-to-T3 more avidly than other tissues. The higher T4 peaks and 24hr serum T4 levels on T4 therapy appear to over-suppress the TSH relative to the thyroid effect obtained. When hypothyroid patients are given a single dose of 50mcg T4, their TSH drops by 25 to 50% but their T3 and T4 levels do not change(76). In many patients with subclinical hypothyroidism, the TSH can be normalized with T4 doses of only 25 to 50mcg, well below the average full replacement dose for a 70kg person of 145mcg/day(77). Reducing the TSH with T4 therapy does not guarantee an increase in T3 levels or affects in the body. The reduction in the TSH causes a proportional reduction in thyroidal T4 and T3 production. In addition, reducing the TSH level also reduces the T4-to-T3 conversion throughout the body. The T4/T3 ratio in PH with a high TSH is double that in CH, when FT4 levels are similar(78). Since approximately 75% of T3 in the serum is produced peripherally from T4-to-T3 conversion(79), this correlation between TSH and T3 strongly suggests causation. In thyroidectomized dogs receiving T4 replacement therapy, TSH-injections raised serum T3 levels to a peak at 12 hours and simultaneously lowered T4 levels(80). The suppression of TSH with T4 therapy in PH and CH further reduces T4-to-T3 conversion. The 40 to 50% higher FT4 levels seen in T4-treated PH patients with vigorous TSH secretion suppress peripheral T4-to-T3 conversion by another mechanism. D2 in skeletal muscle is the source of ≈72% of peripheral T3 production(81). D2 action is suppressed by higher FT4 levels and induced by lower levels, whereas D1 in the liver and kidneys is induced by higher and suppressed by lower FT4 levels(82). D2 suppression also explains why T4 doses that further increase already supraphysiological levels of T4 do not produce proportionate increases in FT3 levels(83). Reverse T3 (RT3) is another part of the explanation. About 40% of T4 produced in the body is usually converted to RT3. This is part of a natural buffering mechanism to prevent excess thyroid effect in the body. It probably evolved in the setting of frequent starvation which characterized much of pre-human and human evolution. RT3 inhibits T4-to-T3 conversion(84). On T4 therapy, RT3 levels are higher than in controls, and are 50% higher than with T4/T3 combination therapy that produces the same TSH level(85). In my experience, many persons on T4 have high RT3 levels, further reducing its effectiveness and leaving them symptomatic. The peak levels seen with oral thyroid replacement may also play a role in over-suppression of the TSH. Endogenous T4 and T3 production are essentially constant over 24hrs, whereas oral dosing delivers the entire day’s hormone into the circulation within a few hours. With once-daily T4 therapy, peak FT4 levels are 13% to 36% higher, and peak FT3 levels are 8% higher at 3hrs than at the 24hr. trough(86, 87, 88). The 24hr. trough FT4 level is higher in most T4-treated patients than in controls. It appears that these unphysiological T4 peaks and levels produce excessive T3 levels in the HP system due to its avid T4-to-T3 conversion, leading to an excessive and prolonged suppression of TSH production compared to endogenous production. In humans, little variation is seen in TSH levels with daily full replacement doses of T4 or T3(89), suggesting that the T4 peaks have a long-lasting effect. In rats, rapid T3 infusions suppress the TSH levels for only 7 hours, whereas rapid T4 infusions suppress the TSH for over 22 hours(90). Only a continuous T4/T3 infusion produces tissue thyroid sufficiency equal to controls without suppressing the TSH(91). It’s possible that this sensitivity to T4 peaks in the serum is an evolutionary adaptation to the occasional excess thyroid hormone ingested by carnivores, in order to avoid hyperthyroidism and its increased caloric requirements(92). Often TSHT4Rx doesn’t even produce mid-range FT4 levels. In my experience, it can even leave FT4 levels low in the range and FT3 levels low. These patients typically remain quite hypothyroid. In patients with known CH, where the TSH cannot be used to guide treatment, merely normalizing the FT4 is insufficient(93). It leaves the FT3 below the range in one-half of the patients(94). The nearly universal weight gain with CH (“hypothalamic obesity”) is iatrogenic; the addition of T3 to T4 therapy produces marked weight loss and resolution of hypothyroid symptoms(95). In CH most guidelines recommend keeping the FT4 above the middle of the laboratory’s reference range. Some experts recommend keeping the FT4 near the upper limit of the range and FT3 in the upper half of the range(96), and others recommend monitoring clinical indices of thyroid action(97). Shouldn’t we give patients with PH the same consideration? Shall we continue to doom them to inadequate treatment because of our faith in their TSH level? 6. The Unfounded Fear of TSH-Suppressive Therapy Due to the official endorsement of the TSH as the “best test”, physicians assume that a low TSH level with T4 monotherapy must have the same physiological implications as a low TSH due to endogenous production. Scientific papers routinely refer to a low TSH on T4 therapy as “subclinical hyperthyroidism”. Therefore physicians avoid any TSH suppression because they believe it will cause all the problems of hyperthyroidism: cardiac dysfunction, atrial fibrillation, bone loss, and muscle wasting. However, we know this is not the case. There is an extensive literature describing the clinical and laboratory findings with TSH-suppressive T4 therapy given to patients who have had thyroid cancer. These studies consistently show no abnormalities or long-term negative consequences as long as the T4 dose is titrated to avoid signs or symptoms of thyrotoxicosis. Patients on physician-monitored TSH-suppressive T4 therapy do not have any increase in cardiovascular disease, dysrhythmias, fractures, or mortality compared to those with normal TSH values(98, 99). The benign effects of TSH-suppressive T4 therapy contrast sharply with the thyrotoxicosis seen in persons with similarly low TSH values caused by endogenous production. One study of endogenous “subclinical hyperthyroidism” found that patients had 15 both symptoms and signs of thyroid excess even thought their TSH was only slightly low at 0.15mIU/L. Both their FT4 and FT3 were in the upper thirds of their ranges(100), a pattern not seen with TSHT4Rx. In overt hyperthyroidism, FT3 levels are high(30). Calorimetry studies of energy expenditure in patients receiving TSH-suppressive therapy after thyroidectomy showed no increase in metabolism compared with the pre-surgical state(101), TSH-suppressive therapy is feared because it is known that excessive thyroid effect in the heart can lower the systolic time intervals(102) and produce a hyperkinetic heart with increased heart rate, excessive cardiac contractility, impaired diastolic relaxation, and thickening of the heart muscle. These changes increase cardiac work, which can be disadvantageous if cardiac blood flow is severely compromised. They also can cause a reduction in exercise tolerance. In one study, a downward adjustment the T4 dose in TSH-suppressive therapy to increase the TSH to 0.01-0.1mIU/L produced a normalization of all echocardiographic and ergometabolic signs of thyroid hormone excess(103). In a study of athyreotic patients with suppressed TSH levels, they had no cardiac symptoms and their cardiovascular studies were similar to controls. The authors concluded that in the absence of symptoms of thyrotoxicosis, patients treated with TSH-suppressive doses of T4 may be followed clinically without specific cardiac laboratory studies. The explanation for the lack of thyrotoxic effect was again found in the FT3 level. The FT4 was above the upper limit of the range but the FT3 was identical to that of the healthy controls(104). Perhaps the main reason given for avoiding any TSH-suppression is the fear of producing atrial fibrillation (AF). It is true that higher thyroid hormone levels, even with the ranges, are associated with increased automaticity and trigger activity in the pulmonary vein myocytes which are known to initiate paroxysmal AF(105). Any increase at all in thyroid hormone levels or effects increases the likelihood of AF in a susceptible person; it does not require overtreatment. In untreated patients, the risk of AF rises from 3% at the bottom of the FT4 range to 7% at the top of the range(106). Thus the decision to increase a patient’s thyroid levels and effects with supplementation always entails a risk of producing AF if he/she is susceptible. Other risk factors for AF include obesity, sleep apnea, and alcohol use. The clinician must weigh the risk of AF in a minority against the benefits of optimal thyroid levels and effects for the majority. Refusing to diagnose hypothyroidism, or treating it with ineffective TSHT4Rx in order to avoid triggering AF is not ethically justifiable. The patient should be informed of the risk and their consent documented. Fortunately, AF induced by thyroid replacement therapy usually resolves with a reduction in FT4 levels, except in older patients with significant underlying heart disease(107). Most physicians believe that TSH-suppressive thyroid replacement therapy causes bone loss and eventually osteoporosis. What is true is that thyroid hormone increases the metabolic rate of all tissues throughout the body, including the rate of bone turnover. If the person is in a net bone-catabolic state, then faster bone turnover speeds bone loss. In such persons hypothyroidism slows bone loss. Hypothyroid females treated with T4 lose bone within the first month, while still hypothyroid, and continue to lose bone over the following 6 months(108). This occurs because most women enter a bone-catabolic state at around age 30(109), probably due to declining estrogen, progesterone, testosterone, DHEA, and growth hormone levels. A review of 21 studies of TSH-suppressive therapy and bone density found that only postmenopausal women were at risk for reduced bone density(110). Estrogen replacement therapy prevents bone loss in women on TSH-suppressive T4 therapy(111). In elderly men a mean thyroxine dose of 130mcg/day has no effect on bone density(112). They apparently have sufficient testosterone and estradiol to prevent bone loss. In adolescent females, TSH-suppressive T4 therapy can even increase bone mineral density compared to controls(113). Here again, the solution is not to keep all patients hypothyroid, but to correct the hormonal or other conditions that have put the patient in a bone-losing state. Muscle wasting is a problem seen only in endogenous hyperthyroidism where both FT3 and FT4 levels are 2 or more times the upper limit of their ranges. Anti-thyroid therapy that raises the TSH to an average of just 0.01mIU/L and lowers the FT3 and FT4 to high within the ranges eliminates muscle breakdown(114). Muscle-wasting is not a relevant concern with physician-monitored thyroid replacement therapy. As with bone loss, muscle loss with higher thyroid hormone levels is a matter of increased metabolic rate. Muscle is broken down for gluconeogenesis if the diet does not supply sufficient calories. 7. The Benefits of Optimal Thyroid Levels and Effects The benefits of treating overt hypothyroidism are well-known. Less well known are the benefits of having higher thyroid hormone levels within the broad ranges and, similarly, of lower TSH levels and higher FT3 levels on T4 therapy. Consider again that the upper and lower limits of the reported FT4 ranges differ by a factor of 2.5 to 3.5, and the FT3 ranges by a factor of 2. Surely there can be marked physiological differences within these broad ranges. The association of hypothyroidism with atherosclerosis is well known, and logically this should also hold for variations within the ranges. Higher thyroid levels ameliorate several risk factors for coronary artery disease. Lowering the TSH to less than 2.0 mIU/L with T4 therapy is associated with lower cholesterol, homocysteine, and CRP levels than simply normalizing the TSH(115). Patients with subclinical hypothyroidism have elevated lipid levels compared to controls and to eliminate the difference requires TSH-suppressing T4 doses(116). A lower FT4 level within the range is associated with hypercoagulability(117). In persons referred for coronary angiography, those with FT3s in the upper third of the range have half the incidence of severe atherosclerosis as those with FT3s in the lower third(118). A T4 dose of 150mcg/d prevents progression of coronary artery atherosclerosis, whereas a dose of 100mcg/d allows progression(119). The negative health and quality-of-life consequences of obesity are well-documented. Optimal thyroid levels help prevent weight gain and promote weight loss. In untreated persons, body mass index and weight gain are associated with lower FT4 values within the range(120), as are four of the five components of the metabolic syndrome(121). Lower FT3 levels within the range are also an independent predictor lower metabolic rate and of weight gain(122). Optimal, not just normal thyroid levels are also beneficial for cognitive function, mood, and well-being. In elderly persons, higher T4 levels within the range were associated with better cognitive function(123) and lower risk of cognitive decline(124). Lower thyroid hormone levels and higher TSH levels within the ranges have been associated with depression or a worse prognosis for remission of depression(125, 126, 127, 128). There are many studies in which T3 therapy alleviated depression in persons with normal thyroid function tests (TFTs)(129, 130, 131, 132, 133, 134, 135 ).Those who respond are more likely to have T4 levels in the lower third of the range(136). In T4-treated PH patients, higher FT4 and lower TSH levels within the ranges are associated with psychological well-being(137). Persons with lower FT4 levels within the range have more complaints of myalgia and muscle weakness and have lower muscle strength(138). 80% of persons with hypothyroid symptoms but normal TFTs experience improved mood and energy on an average levothyroxine dose of 125mcg/day(139). Ignoring the abundant objective evidence for the physiological and psychological benefits of having higher free hormone levels within the ranges, some claim that those with normal TFTs who experience subjective improvement on thyroid replacement therapy must have a “thyrotoxic euphoria”. This ad hoc diagnosis is inconsistent with the evidence of physiological benefits given above, and with the fact that patients feel worse, not better when they have excessive thyroid hormone levels. Studies of endogenous hyperthyroidism, TSH-suppressive therapy, and fixed T3-for-T4 substitution show that excessive thyroid supplementation reduces one’s quality of life. When symptomatic persons and asymptomatic controls, all with normal TFT’s, were given 100mcg of T4 daily, the controls experienced thyrotoxic symptoms and their T3 and T4 levels increased more within the ranges than those who had hypothyroid symptoms(140). Likewise, a group of patients with endogenous “preclinical hyperthyroidism” (low TSH with high-normal FT4) displayed the same negative, undesirable symptoms as a group of hyperthyroid patients(141). Hormones are not drugs. There is no substitute for diagnosing and treating according to clinical criteria. A level of thyroid hormone supplementation that makes an individual feel and function better and produces no signs or symptoms of excess should be considered beneficial and necessary until proven otherwise. 8. The Greater Efficacy of T4/T3 Combination Therapy The elevation of the TSH in the face of thyroid gland dysfunction is a compensatory mechanism, stimulating more hormone production and greater T4-to-T3 conversion throughout the body. TSH and TRH also directly induce mitochondrial biogenesis and activity(142, 143). Lowering the TSH levels with thyroid replacement therapy interferes with these homeostatic mechanisms, reducing both thyroidal T4 and T3 production and T4-T3 conversion throughout the body. When resorting to replacement therapy, the physician bears the responsibility of fully restoring and optimizing T3 levels and effects throughout the body. It is thus only logical that thyroid replacement therapy should include T3. The effects of T4, T3 and combination therapy on various tissues were revealed in an elegant series of experiments performed on rats. The investigators determined both serum and post mortem tissue levels of T4 and T3 in rats receiving continuous infusions of various combinations of the two hormones. A T3-only infusion failed to restore T3 levels in all tissues—illustrating the importance of T4 and peripheral T4-to-T3 conversion(144). A continuous T4-only infusion also failed to restore serum and tissue T3 levels to those of controls in all tissues until T4 levels were raised into the supraphysiological range and TSH was suppressed(145). The addition of T3 to a T4 infusion in the same ratio produced by the rat’s thyroid gland (1:6) allowed a normalization of both serum and tissue levels of both hormones without suppressing TSH(146). The human thyroid produces T3 and T4 in a lower 1:14 ratio(147). If we could give T4 and T3 by continuous infusion, mimicking thyroidal production, we might be able to use this ratio and might only need to normalize the TSH. However, it is clear that once-daily oral therapy produces a relative over-suppression of TSH production, and therefore of T3 production thoroughout the body, so we need to provide more T3. We are fortunate to have many studies that compare various T4/T3 combinations with T4-only therapy. These studies provide abundant detailed clinical data on the effects of substituting various amounts of T3 for T4. In all but four of fourteen studies, the authors concluded that T4/T3 combination therapy offered no advantage, however the studies comprise a mixed bag of undertreatment and overtreatment, and one can come to a very different conclusion upon reviewing the data. Statistical conclusions can be misleading. If one-half of the patients demonstrated improvement and one-half deteriorated, the result is no overall benefit. There is a 3-fold range in the relative potency of T3 to T4 in different subjects treated with both hormones(148), so any fixed combination is going to have different effects in different persons. Arbitrary substitutions can produce over-replacement in some persons and under-replacement in others. Persons with some degree of hypocortisolism will not tolerate sufficient thyroid replacement. The T4/T3 combination studies were created and interpreted according to TSH-FT4 reference range paradigm. They usually involved arbitrary substitutions of some amount of T3 for the treated patients’ T4 dose. In only one study, the first, was the T4/T3 dose adjusted by clinical criteria. In many studies the doses of T4 and/or T3 were adjusted to maintain a normal or specific target TSH. From looking at the detailed results of these studies one can draw the following conclusions: (See Appendix) Patients on TSH- or T4-normalizing doses of T4 usually have higher symptom scores than controls, as noted in other studies. They are undertreated. Arbitrary substitutions of some amount of T3 for T4 can produce under- and over-replacement in a significant number of patients. At any given TSH level, T4/T3 combination is more effective than T4 monotherapy, both in objective scales and signs and in patient preference. Low TSH levels on therapy are usually associated with better clinical effects, both with T4 and with T4/T3 combination therapy, but some patients do not tolerate TSH-suppressive doses of either therapy. Persons with a low-normal or suppressed TSH level on T4 experience the greatest improvement with adding T3 to their regimen, less improvement is seen when TSH levels are higher in the range. There is no support for the contention that T3 therapy is dangerous or causes problems due to the fluctuations in free T3 levels, even with once-daily therapy. The T4/T3 combination studies support the hypothesis that the addition of T3 to T4 therapy is beneficial for most if not all patients, and they illustrate the need for clinical thyroidology—for the adjustment of either T4 or T4/T3 combination therapy to produce optimal clinical effects for each patient, without regard for the TSH level. The benefit of adding T3 is greatest when the TSH is lowest, consistent with the fact that TSH stimulates T4-to-T3 conversion throughout the body. In its absence supplemental T3 is needed. Some persons may require more T3 relative to T4 than others, or even exclusive T3 therapy. Around 16% of the population has a genetic polymorphism of their deiodinase 2 gene producing impaired T4-to-T3 conversion. They have lower quality of life scores on T4 therapy and significant improvement with the addition of T3 to their regimen(149). There may be many other such polymorphisms. Many patients diagnosed with fibromyalgia have a form of hypothyroidism that responds well to T3-only therapy(150, 151, 152). 9. Clinical Diagnosis and Therapeutic Trial Neither diagnosis nor treatment can be left up to the laboratory. The physician is responsible to consider the complexity of the hormonal system and to use his/her judgment. Due to the almost exclusive reliance on the TSH, most physicians now have no experience with either the clinical diagnosis or treatment of hypothyroidism. The diagnosis of any disease or disorder is rarely 100% certain. In most cases the diagnosis is a theory. The physician weighs all the evidence and creates the best theory to explain the signs and symptoms. Tests may support or weaken the theory. The ultimate test is a therapeutic trial. A positive response greatly strengthens the theory, and the sustained elimination of signs and symptoms strengthens it even more. Clinical thyroidology requires listening to the patient’s symptoms, querying them for the presence of other thyroid-related symptoms, and looking for physical signs. The physician should also look for any other medical causes that may explain the symptoms. A frequently-overlooked problem that can mimic hypothyroidism is iron deficiency. It is very common in women and appears, among its many effects, to interfere with thyroid levels and effects(153). Studies show that non-anemic women with fatigue and ferritin levels under 50 mcg/L experience improved energy(154, 155) and mental function(156) with iron replacement therapy. Initial thyroid testing should include a FT4, FT3 and TSH level. The TSH is not needed for initial testing, but it is inexpensive and readily available. It provides immediate evidence of HP function and prevents the patient from needing an additional blood draw to investigate the cause. Thyroid antibody testing should be reserved for determining the cause of primary hypothyroidism. The other labs test of some interest is the lipid profile. Elevated total and LDL cholesterol levels should be considered a possible sign of hypothyroidism. In my experience, T4/T3 thyroid optimization therapy reliably produces marked declines in total and LDL cholesterol levels. Diagnosis requires clinical suspicion. While there are classical signs and symptoms of hypothyroidism, some persons may have only one symptoms, or symptoms that are not classical. If the patient has some combination of symptoms and/or signs of that could be due to hypothyroidism, and has relatively low FT4 and/or FT3 levels, then the physician should offer the patient a trial of thyroid optimization therapy, regardless of the TSH level. The greater the number of hypothyroid symptoms and the lower the FT4 and FT3 levels, the more certain is the diagnosis and the response to therapy. Certainly, any person with fatigue, myalgias and arthralgias, depression, and/or cognitive dysfunction with no other obvious cause and with relatively low thyroid hormone levels should be offered a trial of thyroid hormone optimization. The physician whould see if higher thyroid levels and effects will ameliorate the patient’s symptoms and signs. If the patient experiences no benefits or feels worse, then either they do not have hypothyroidism, or they have hypothyroidism and some degree of adrenal insufficiency (hypocortisolism). It is well-known that thyroid replacement worsens adrenal insufficiency, but what is not appreciated is that this fact applies to all degrees hypocortisolism, not only to cases of obvious Addison’s disease or known HP disease. As a tertiary specialist, the majority of patients who consult me with symptoms of hypothyroidism have normal TSH levels—untreated or treated. I find that the FT4 is usually the most sensitive test of thyroid status in an untreated person(157), Untreated symptomatic patients usually have a relatively low FT4 level between 0.8 and 1.2ng/dL (unscreened population range 1.0-1.6ng/dL) and a mid-range or low-in-range FT3 level. The FT3 less sensitive because it is often maintained, in the face of rather low FT4 levels, by TSH elevation and enhanced peripheral T4-to-T3 conversion. A low-normal or low FT3 occurs when the FT4 is very low, when compensatory mechanisms are not working, or when the person has some other metabolic problem (euthyroid sick syndrome). A person with both a low-normal FT4 and low-normal FT3, treated or untreated, can be markedly hypothyroid. All TSH-normal symptomatic patients who respond to a trial of supplementation have, by definition, some degree of dysfunctional central hypothyroidism. They may also have an inadequate response of their thyroid gland to TSH—mixed central/primary hypothyroidism. T4-only therapy may be sufficient for some at an optimal dose that produces sufficient T3 levels and effects, but questioning of TSHT4Rx patients often reveals persisting hypothyroid symptoms: the need to nap every afternoon, constipation, cold intolerance, inability to lose weight with effort, poor memory and concentration, high cholesterol levels, etc. In patients who remain symptomatic on T4, the FT4 is usually mid-range, sometimes low-normal, and FT3 levels are low-normal or low. The RT3 is often high-normal or high. In my experience, TSH-normal patients, untreated or treated, with hypothyroid symptoms and rather low thyroid hormone levels usually respond well to effective treatment. Others have reported the same(158). There have been no real studies. Symptomatic patients with normal TFTs were given a fixed dose of 100mcg of T4. This dose decreased the TSH to a lower point within range, increased the free T4 only slightly, and did not significantly raise the FT3. The authors concluded that treating such patients brings no benefits(159). Such inadequate trials tell us nothing about the benefits of thyroid optimization. The question is, what constitutes a trial of effective thyroid replacement therapy(23)? 10. T4/T3 Thyroid Optimization Therapy Having dismissed the current TSH-based treatment of hypothyroidism, it behooves me to describe the practice of clinical thyroid optimization. I have 9 years experience with optimizing T4/T3 dosing according to clinical criteria and free hormone levels, without regard to the TSH, in nearly a thousand patients. I have found that with T4/T3 combination therapy, as with T4 therapy, one should start with a relatively low T4/T3 dose and increase it gradually until sufficient benefits are achieved, or until signs and symptoms of overdosing appear indicating a need to reduce the dose. Some clinical symptoms and signs of overdosing are listed in Table 2., many others may be seen. Simply put, if the patient feels persistently worse in any way rather than better, then that dose, at that time, is excessive for that patient and should be lowered, at least temporarily. Frequently patients will later need and benefit from doses they did not tolerate earlier. The thyroid dose usually must be increased a few times in the first 3 years of treatment, especially with TSH-suppressive therapy, as thyroid levels on the same dose will fall in the first years(160). This is probably due to the gradual atrophy of the thyroid gland and down regulation of D2 and D1. Table 2. Signs and Symptoms of an Excessive Thyroid Dose Any increase in malaise or fatigue Heat intolerance Excessive sweating Irritability, inability to relax Hand tremor Fatigue Lower exercise tolerance Pressured speech Pupillary dilatation Insomnia Palpitations or rapid heart rate Frequent premature atrial or ventricular contractions For persons already on TSHT4Rx who are symptomatic, one can simply add 5mcg of T3. Depending on the patient’s medical situation, one can increase the T3 dose by 5 mcg every 2 weeks up to 15mcg before testing. T3 has a half-life less than 24hrs, so steady-state concentrations are reached within 1 week and most effects felt within 2 weeks. What should be the ideal proportion of T4/T3 for oral thyroid replacement? Even though the human thyroid excretes T4 and T3 in a ratio of 14:1, once-daily oral replacement requires a lower ratio (more T3) due to the over-reduction in TSH and in T4-to-T3 conversion throughout the body. This fact explains the popularity and efficacy of natural dessicated thyroid (NDT) products. Those of porcine origin contain T4 and T3 in a 4:1 ratio. 60mg of NDT contains 38mcg of T4 and 9mcg of T3. The lower T4/T3 ratio assures sufficient availability of T3, the active thyroid hormone. NDT is a fixed T4/T3 combination product that is readily available, convenient, inexpensive, and contains T2 which has metabolic activity(161, 162, 163). Fortunately, NDT has finally been compared to T4 therapy in a randomized, double-blind, crossover study. The differences favored NDT. There were no adverse effects with either treatment(164). I have found it most efficient to begin otherwise healthy patients on NDT at 30mg daily upon awakening and to increase the dose by 30mg every week or two up to 120mg. I then wait 6 to 8 weeks to test and adjust the dose by symptoms, signs and the FT4 and FT3 levels. Blood should be drawn in the morning, prior to taking morning dose. On NDT in contrast to T4 therapy, FT4 levels will remain relatively low and FT3 levels relatively high. FT3 levels are high at their peak 3 hrs post dose and fall gradually to the 24hr trough. Most persons who are well replaced on once-daily NDT therapy will have, at the 24 hr. trough, a FT4 of around 1.1 to 1.3 ng/dL, a FT3 that is in the upper third of range or even slightly high, and a suppressed TSH. A high FT3 during the day, and even at the 24hr trough is acceptable as it compensates for the rather low amount of FT4 in the serum and low T4-to-T3 conversion with TSH-suppression. FT4 circulates in amounts 500 times greater than FT3. Excessive NDT dosing may produce a FT4 that is high in the range and a FT3 that is also high-normal or high at the 24 hr trough. The RT3 level can be helpful in detecting overtreatment. When the NDT dose is excessive, the body will protect itself by converting more of the T4 into RT3. A normal RT3 on NDT therapy provides some reassurance that the dose is not excessive. However, FT4 and FT3 levels are only second-rank indicators of end-organ effect. The primary determinant of optimal dosing must always be the patient’s signs and symptoms. Some patients will require doses that produce high free thyroid hormone levels, and a few will require T3-only therapy. On T3 only, laboratory tests are completely useless as the FT3 must be above the range at all times, including at the 24 hr. trough. Superphysiological T3 levels are necessary at all times to compensate for the absence of the much more abundant T4. Once-daily AM dosing with T3 or NDT generally works fine, but there are some patients will do better with splitting the dose. Some persons may do better with a higher T4/T3 ratio and others with a lower T4/T3 ratio. Different T4/T3 ratios can be obtained by using levothyroxine and liothyronine, or by adding one of these to NDT. There is no substitute for clinical thyroidology. The physician must work with the patient to find the most effective thyroid replacement regimen that eliminates the symptoms signs of hypothyroidism without producing any clinical evidence of overdosing. I never cease to be amazed at how consistently thyroid optimization helps patients, and at the many and various improvements that patients report. I believe that physicians will obtain much satisfaction from restoring their patients’ quality of life and functionality by diagnosing and effectively treating their hypothyroidism. Appendix: Review of T4/T3 Studies Taylor 1970(165): Thyroidectomized patients were treated with T4/T3 in ratios of 9:1, 4:1, and 3.3:1. Only the 3.3:1 ratio produced both optimal clinical effects and a normal protein-bound iodine (PBI) level—a reflection of total T4 plus total T3. Patients generally felt better on T4/T3 combination therapy. Comment: This is the only study that adjusted both the doses and ratios of T4 and T3 to optimal clinical effect, not to the TSH, which was not available at the time. The optimal combination had a much lower T4/T3 ratio (3.3:1) than that produced by the human thyroid gland (estimated at 10:1 to 14:1). With the 9:1 ratio, clinical euthyroidism was not achieved without elevation of the PBI. This suggests that oral therapy requires a lower T4/T3 ratio than thyroidal production to compensate for the reduced production of T3. Smith 1970(166): Each 100mcg of T4 was replaced with 80mcg T4 plus 20mcg T3. Given the T4/T3 oral equivalence ratio of 1:3.3, this was a nearly 50% dose increase. Combination treatment predictably produced negative effects in many patients, yet half of the subjects noted no preference for either treatment, and 1 in 5 preferred the combination. Comment: This was a case of excessive T3-substitution in patients already taking rather high-doses of T4. Cooke 1982(167): An open-label T3 add-on study of depressed patients on T4 therapy whose TSH levels were low-normal. 15 to 50mcg of T3 was added to the patient’s T4 dose. There was objective and subjective improvement in mood in 7 of 9 patients. Comment: Adding T3 to a patient’s TSH-normalizing T4 dose improves mood. Bunevicius 1999(168): Half of the subjects were on suppressive therapy for thyroid cancer with very low or undetectable TSH levels. The average TSH was 0.8mIU/L. 50mcg of the usual T4 dose was replaced by 12.5mcg of T3, an equipotent 4:1 substitution producing a 10:1 ratio. (26) The average TSH decreased slightly from 0.8 to 0.5mIU/L. There were improvements in fatigue and some cognitive tests. Patients preferred combination therapy over T4 by 10:1. Comment: With substitution, FT4 and FT3 levels were more similar to those of normal persons. The positive results of this study indicate that T3 may be especially helpful when a patient is on TSH-suppressive T4 therapy and thus has less T4-to-T3 conversion. Walsh 2003(169): 50mcg of the patients’ T4 dose was replaced with 10 mcg of T3 (a 5:1 under-substitution). With combined treatment, the TSH rose from 1.5 to 3.1mIU/L. The trough FT3 level did not change and remained relatively low at 3.5pmol/L (range: 3.0-5.5pmol/L). There was no improvement in scales and some deterioration seen in the general health questionnaire. More patients preferred T4 than combination treatment. In the subgroup whose TSH did not rise by more than 0.99mIU/L, more preferred combination therapy. On combination therapy, the SHBG was lower and cholesterol higher, indicating reduced thyroid effect. Comment: The 5:1 substitution produced undertreatment as indicated by the increase in TSH, deterioration in scales, and patient preference. Those whose TSH rose the least favored combination treatment, suggesting that at a given TSH level, T4/T3 therapy is more effective. Sawka 2003(170): Patients had depressive symptoms. They were given half their usual dose of T4 plus 12.5mcg of T3 twice daily. The dose of T3 was adjusted to maintain nearly equal TSH concentrations in both groups. At baseline, the T4 group was more undertreated as indicated by an avg. TSH of 2.2mIU/L compared 1.75 mIU/L for the study group. With study treatment, the avg. TSH in the T4 group declined by 0.5mIU/L, but rose by 0.1mIU/L in the T4/T3 group. There were improvements in both groups, but greater improvements in the T4/T3 group, especially in cognitive functioning, role-physical, and social functioning scales. Comment: The T4 group received a higher effective dose, explaining their improvements in the scales. In spite of a slight increase in TSH, the T4/T3 group had greater improvements across the board. In their commentary, the authors ignored the differences in pre- and post-study TSH levels and the greater improvements in the study group. Patients were not asked which treatment they preferred. (27) Clyde 2003(171): The patients’ usual dose of T4 was reduced by 50mcg and they were given 7.5mcg of T3 twice daily. This was an approximately equipotent 3.3:1 substitution. The T4 dose was adjusted in both groups to keep the TSH between 0.5 and 3.5 mIU/L. The resultant TSH was slightly lower in both groups (≈2.0 mIU/L). Both groups improved in most scales with no substantial overall differences between them. Total cholesterol and LDL did decrease in T4/T3 group and increase in the T4 group. Comment: A study of TSH-normalizing therapy with a relatively high TSH on replacement. All study patients were under-replaced on TSHT4Rx at the beginning of the study as demonstrated by FT4 levels below the midpoint of range and FT3 levels near bottom of the range, and at the end of study, both groups still had worse hypothyroid quality-of-life ratings than controls (54 vs. 40). In this study there was little difference between these two under-replaced groups with similar TSH levels. Patients were not asked which treatment they preferred. Siegmund 2004(172): 5% of the patients’ T4 dose was substituted mcg for mcg with T3 (5 to 8mcg T4 was replaced by 5 to 8mcg T3). The avg. TSH of 1.72mIU/L declined to 1.5mIU/L in the T4 group and to 0.5mIU/L in the T4/T3 group. The FT4 was 22pmol/L at baseline–high normal (range 10-25pmol/L). Some patients became overdosed on combination therapy. Mood was significantly impaired in 1/3rd of those whose TSH was completely suppressed (<0.02mIU/L). Removing these patients from the Beck Depression Inventory (BDI) scales revealed an improvement from 7.8 to 4.07 for the combination group compared to 6.9 in the T4 control group. Even including the 1/3 of subjects who had negative reactions, the BDI and some other subjective and objective scales improved on the T4/T3 combination. Comment: A 1:1 substitution study, essentially a T3 add-on study. Patients were already on a relatively high-dose of T4 with FT4 levels near the upper limit of the range. The add-on T3 caused negative symptoms in 1/3rd of the subjects—skewing the overall results. Because those patients had lower TSH levels, the authors concluded that combination therapy can cause subclinical hyperthyroidism, even though their FT4 and FT3 levels were similar to the rest. They blamed the impaired well-being on fluctuations in T3 levels; when the only finding they attempted to relate to T3 fluctuations was a greater suppression of the TSH. The authors ignored the fact that the negative reactions of a subset of patients with this T3 add-on therapy produced the bulk of the undesirable results. The lesson of the study is that 28 Individual tolerance for thyroid replacement therapy varies greatly. There is no substitute for clinical T4 or T4/T3 dose adjustment. Escobar-Morreale 2005(173): A low average T4 dose of 100mcg was replaced with 75mcg of T4 + 5mcg of T3, a 5:1 under-substitution. In an 8-week T3 add-on period, all patients received 87.5mcg + 7.5mcg T3, a 1.7:1 over-substitution. TSH levels were 1.95mIU/L on 100mcg T4, 2.65mIU/L on low-dose combination therapy, 1.09mIU/L on the add-on combination therapy. Patients preferred T4/T3 combinations over T4 alone by a ratio of 9:1. The visual analog scale for depression for all treatment groups was higher than that of controls, and showed improvement only in the add-on combination group. Comment: Another TSH-normalizing study in which most patient were under-replaced. T4/T3 combination therapy produced objective improvements and was preferred by patients. Appelhoff 2005(174): Patients had low-normal TSH levels. The T4 dose was reduced and T3 added to produce an overall T4/T3 ratio of 10:1 or 5:1. Study medication was preferred to usual treatment by 29.2, 41.3, and 52.2% in the T4, 10:1 ratio, and 5:1 ratio groups, respectively. The median endpoint TSH values in the three groups were 0.64, 0.35, and 0.07mIU/L. Objective testing revealed no differences except for a mean body weight change of +0.1, -0.5, and -1.7kg, respectively. Those who preferred the addition of T3 had suppressed TSH levels (0.35 and 0.07 mIU/L) and lost more weight. Comment: These patients were already on a relatively high dose of T4 compared to most (avg. TSH 0.64mIU/L). Even so, equipotent substitution (1mcg of T3 for 3.3mcg of T4) produced subjective improvement, and superpotent substitution (3mcg of T3 for 5mcg of T4) produce greater reported improvement and weight loss. Notice also that no deleterious effects were noted with the suppression of the TSH to 0.07mIU/L. Rodriguez 2005(175): 10mcg of T3 was substituted for 50mcg of T4; an inadequate 1:5 substitution and an effective reduction in dose. The avg. baseline TSH was 1.9mIU/L. Some symptom scores worsened as the TSH increased to 2.7mIU/L in the substitution group. Even so, 12 preferred the substitution treatment compared to 7 for the standard treatment. (29) Comment: A 5:1 T4/T3 substitution increased both TSH values and symptom scores. In spite of this more patients preferred the T4/T3 combo than T4 only. This indicates that T3 has benefits that are not reflected in the TSH level. Slawik 2007(176): TSH was not followed as patients had central hypothyroidism. Patients were on low-dose T4 therapy (1.1mcg/kg/d). They were randomized and crossed-over to receive 1.6 mcg/kg/d of T4 or 1.44mcg/kg/d plus 0.16mcg/kg/d of T3. Given a T4/T3 potency of 3.3/1, the T4/T3 combo produced a higher T4-equivalent dose. Both the higher BW-adapted T4 dose and the combination therapy reduced hypothyroid symptoms, but the combination therapy produced greater reductions in muscle CK and ankle reflex time. There was no increase in any negative symptoms (i.e. thyrotoxicity) on the T4/T3 combination. Comment: A higher, more appropriate T4 dose produced high-normal or high FT4 levels and eliminated most hypothyroid symptoms and signs. The addition of T3 with a slightly lower amount of T4 brought more improvements without signs or symptoms of overdosing. Interestingly, T4 levels did not decline with the reduction in T4 dose in the T4/T3 group, indicating a reduction in T4-to-T3 conversion when sufficient T3 is supplied. Nygaard 2009(177): TSH normalizing-study performed on Hashimoto’s patients on T4 therapy with low-normal TSH levels (≈0.1mIU/L). 20mcg T3 was substituted for 50mcg T4, a 1:2.5 over-substitution) then the T4 dose was adjusted to keep the TSH low-normal. The resultant TSH in the T4/T3 group was slightly lower than T4 group. (0.7 vs. 0.9mIU/L). Significant improvements were seen in the T4/T3 group in 7 of 11 measures of quality of life, anxiety and depression. There was an average weight loss of 3.3lbs on combination therapy and patients preferred combination therapy by a ratio of 3.3:1. Comment: More benefit seen than in most T4/T3 studies because the T3 dose (20mcg) was higher and the treatment TSH was near the bottom of the range. There was no difference in adverse effects between treatment arms. The T4/T3 ratio was ≈4:1, similar to that of natural dessicated thyroid (NDT). This is more evidence that at the same low-normal TSH, 4:1 T4/T3 combination therapy is superior to T4 therapy. Hoang 2013(178): A TSH-normalizing study in which patients on T4 were randomized to receive NDT (Armour Thyroid) then crossed over. The TSH levels were slightly higher than in Nygaard study. The average NDT dose was equivalent to only 50mcg T4 and 12mcg T3; far lower than in Nygaard. In T4-treated patients, the RT3 level was at the top of the range, with NDT it was reduced to mid-range. The patients on NDT lost 3lbs on average, and 49% of patients preferred NDT vs. 19% for T4. There were non-significant trends towards improved quality of life and better neuropsychological test scores, especially among those who preferred NDT. There were no adverse effects noted with either treatment. Comment: This is the only randomized TSH-normalizing study of NDT vs. levothyroxine. The differences favored NDT. There were no adverse effects with either treatment. The equivalent potency ratio of T4 to NDT to produce a similar TSH level was 1.5mcg T4 ≈ 1mg NDT. References: Greenspan FS, Rapoport B. 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Written by: Wakako Jo(1) Katsura Ishizu(1) Kenji Fujieda(2) and Toshihiro Tajima (1) 1 = Department of Pediatrics, Hokkaido University School of Medicine, N15, W7, Sapporo, Hokkaido 060-8638, Japan 2 = Department of Pediatrics, School of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido 078-8510, Japan Abstract Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH) due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD). Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although I scintigraphy (1, 2, 3) at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS) gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis. 1. Introduction Congenital hypothyroidism (CH) is the most common congenital endocrine disorder and occurs at rate of 1 in 3000–4000 births [1]. The causes of CH can be classified into two groups: thyroid developmental defects (thyroid dysgenesis) and inborn errors of thyroid hormone biosynthesis (dyshormonogenesis). Several genes responsible for thyroid dysgenesis have been identified such as TSHβ-subunit, TSH receptor, the Gs α-subunit, TTF-1, TTF-2, GLIS3, and PAX8 [2]. Among them, PAX8 is a paired domain transcription factor and is expressed in the developing thyroid, kidney, and several areas of the central nervous system [3]. In addition to its role in normal thyroid development, PAX8 regulates the expression of genes encoding thyroglobulin (TG), thyroid peroxidase (TPO), and the sodium-iodide symporter (NIS) by binding to their promoter regions through its 128-amino acid paired domain [4, 5]. To date, several mutations of the PAX8 gene have been identified in CH patients [6–12]. Most of these mutations have caused thyroid dysgenesis; however, some patients with PAX8 mutation have a normal-sized thyroid gland [9, 10]. Iodide transport defect (ITD) is a rare disorder characterized by an inability of the thyroid to maintain a concentration difference of readily exchangeable iodide between the plasma and the thyroid. Diagnostic criteria for ITD include a variable degree of CH and goiter, low or absent radioiodide uptake, as determined by thyroid scintigraphy, and low iodide saliva to plasma (S/P) ratio [13, 14]. This disease is caused by mutations of the NIS gene [13–17]. Here we report that a patient with a PAX8 mutation showed low iodide S/P ratio. The PAX8 mutation in this patient manifested as CH due to ITD. 2. Case Report A male infant was born after full-term gestation by normal vaginal delivery from nonconsanguineous parents. His birth weight was 3342 g. The family history revealed no thyroid disease. There were no abnormal physical findings; however, neonatal mass screening using filter paper for congenital hypothyroidism at the age of 6 days showed a high level of thyroid stimulating hormone (TSH) (62.8 mU/L, normal <10 mU/L). The patient was referred to our hospital at the age of 17 days for further evaluation. At that time his body weight was 3950 g. Physical examination did not show any abnormal findings including goiter. Biochemical evaluation revealed that the serum TSH level was 202.7 mU/L, thyroxine, 91.3 nmol/L, and triiodothyronine, 1.88 nmol/L (Table 1). He was treated with levothyroxine (L-T4) at that time. At the age of 5 years, he underwent 123I scintigraphy after the discontinuing L-T4 treatment for one month. Although 123I scintigraphy showed a normally located thyroid gland, his 1-, 3-, and 24-hour 123I uptake values were 4.8%, 5.8%, and 2.9%, respectively (normal range,10%–30%). 123I S/P ratios at 2 and 4 hours were 4.5 and 3.8, respectively (normal >20) (Table 1). He did not have goiter; however, his diagnosis was considered to be partial ITD based on low thyroidal iodide uptake and low S/P ratio. The patient is currently 23 years old, and he has never developed goiter during follow-up. Table 1 Laboratory findings in the patient: Values of filter paper at neonatal screening: TSH (mU/L) (normal range 0.1~10) 62.8 Values at the time of the first evaluation (Serum): 17 days of age TSH (mU/L) (normal range 0.34~3.5) 202.7 T4 (nmol/L) (normal range 59.2~161.2) 91.2 T3 (nmol/L) (normal range 1.22~2.76) 1.88 I thyroid scan at 1, 3, 24 h 4.8, 5.8, 2.9 Saliva/Serum ratio at 2 h and 4 h 4.5, 3.8 Thyroid scan was performed at age of 6 years 3. Method After obtaining written consent from the patient and the patient’s parent, genomic DNA was extracted from peripheral blood lymphocytes. The NIS and PAX8 genes were amplified by polymerase chain reaction (PCR) according to previously-described methods [6, 17]. After PCR amplification, the amplified products were subjected to direct sequencing. 4. Results Analysis of the NIS gene revealed no nucleotide changes in the coding region nor in the exon-intron boundaries. Upon analysis of the PAX8 gene, we identified the patient washeterozygous for an arginine (CGC)-to-histidine (CAC) substitution at codon 31 (R31H), which was previously reported in a patient with CH [6] (Figure 1). 5. Discussion In the present study, we reported a Japanese patient with R31H substitution in the PAX8 protein. Since the arginine at residue 31 is located in the paired domain in the PAX8 protein and is conserved among species, this amino acid substitution is thought to impair its DNA-binding activity, resulting in loss of function. It is of interest that a mutation at this residue was previously found in one Italian patient and one Japanese patient [6, 7]. These two patients were diagnosed as having thyroid hypoplasia as determined by ultrasonographic examination. We also identified R31H in another Japanese CH patient who had hypoplastic thyroid (unpublished data). To determine whether or not substitution of this arginine is frequent among Japanese patients with CH, further analysis is required. Defective mutations of the PAX8 gene have been considered to mainly cause thyroid hypoplasia. However, clinical heterogeneity has bee observed among patients and even in the same family [9, 10]. One patient who had S54G substitution in of the PAX8 protein had organification defect and a normal-sized thyroid [10]. Since PAX8 plays a critical role in TPO expression during thyroid development [2, 4], impaired TPO gene expression due to PAX8 dysfunction may have led to organification defect in that patient. In this context, it may be possible that NIS expression is affected by mutations of the PAX8 gene, because a PAX8 binding site was found in the far-upstream enhancer region of the human NIS gene and PAX8 was required for activation of NIS gene expression in the thyroid [18]. As mentioned earlier, the hallmarks of ITD are markedly reduced or absent thyroidal uptake of radioiodide and reduced iodide S/P ratio. Absence of thyroidal iodide uptake is a typical feature of thyroid agenesis, and thus diagnosis is erroneously assigned to some patients with iodide trapping defect, especially when goiter was not present. Szinnai et al. [14] summarized the clinical features, laboratory findings, and mutations of the NIS gene in patients with ITD. Among these 31 patients, radioiodide uptake ranged from <1% to 4.8% and the iodide S/P ratio ranged from 0.94 to 5.2. Regarding goiter, 18 patients developed goiter and its diagnosis was made at a median age of 11 years. In our patient, the value of radioiodide uptake was higher than that in previously reported patients. However, the iodide S/P ratio in our patient was low. An iodide S/P ratio in the vicinity of 1 is considered to be the consequence of complete ITD while an iodide S/P ratio of up to 20 is considered to represent partial ITD [13]. Therefore, we initially speculated that the cause of CH in our patient was partial ITD due to defective NIS. However, sequence analysis showed that the NIS gene was normal; instead a mutation causing R31H in the PAX8 protein was found. As mentioned earlier, PAX8 gene expression during the fetal period is observed in the developing thyroid and kidney during human development [3]; however, its expression in salivary glands has not been examined. It is tempting to speculate that PAX8 is expressed and enhances NIS gene expression during embryogenesis in the human salivary glands similar to in the thyroid gland. Thus, PAX8 mutation may impair NIS function not only in the thyroid but also in the salivary glands. This possibility must be studied further. 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View at: Publisher Site | Google Scholar Received 22 Jun 2009 Accepted 20 Sept 2009 Published 09 Dec 2009 Case Report | Open Access Volume 2010 | Article ID 619013 | https://doi.org/10.4061/2010/619013