NHS UKMi Q&A 56.5 (November 2011) TPA REBUTTAL
Thyroid Patient Advocacy (TPA) Response to UKMi Q & A (56.5) “What is the rationale for using a combination of levothyroxine and liothyronine (such as Armour Thyroid) to treat hypothyroidism?”
TPA finds that some of the statements made by UKMi are misleading, inadequate, and in parts, incorrect. TPA has provided additional relevant clinical information which we hope will be taken into consideration.
UKMi: Background – first sentence is misleading: levothyroxine (T4) is converted to triiodothyronine in peripheral tissues, providing stable and physiological quantities.
This should read levothyroxine (T4) is normally converted to triiodothyronine for correctness.
Although T4-only can partially mitigate symptoms for many, the results of a large UK study show that between 9% and 15% of patients prescribed T4-only continued to suffer symptoms that might, in some way, be related to their T4 only therapy. There are approximately 300,000 patients in the UK who do not benefit from this therapy. Peripheral thyroid hormone physiology exists and these patients should not be given a diagnosis of Hypothyroidism or treated with T4-only.[2-4]
Part of the problem lies with defects in the Royal College of Physicians (RCP) Teaching Curriculum, the GMC Endocrine Curriculum, and The Map of Medicine (MoM)  which give no guidance regarding recommended diagnostics and treatment of Euthyroid Hypometabolic Syndrome (EHM) despite the need for other thyroid hormones for some patients. Also, there are limitations to the interpretation of serum thyroid function testing. Taken together, these defects in the medical approach to symptoms of hypothyroidism cause an enormous disservice to patients who are placing their trust in the ability of the medical profession to properly apply what science tells us about thyroid physiology and biochemistry.
The UKMi pharmacists report is ONLY about those patients suffering with HYPOTHYROIDISM (under activity of the thyroid gland) which can, in most cases, be treated successfully with levothyroxine (T4) only. A logical examination of a continuing medical education course  and The Linguistic Etiologies of Thyroxine-resistant Hypothyroidism  find that the concepts of hypothyroidism and thyroid hormone therapy are unclear in current teaching and Medical Practice Guidelines. Pritchards peer-reviewed Paper ‘Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism' exposes the above defects showing that endocrinology ignores those patients with deficient peripheral metabolism or increased peripheral hormone receptor resistance in their thyroid-only testing and therapy.
The RCP defines hypothyroidism as: The clinical consequences of insufficient secretion by the thyroid gland., which can, in most cases be successfully treated with levothyroxine-only. But, it states. In patients with suspected primary hypothyroidism there is no indication for the prescription of T4 or any preparation containing thyroid hormones to patients with thyroid blood tests initially within the normal range, which ignores the potential for euthyroid hypometabolism or other post-thyroid deficiencies. 
However, the broader and more helpful definition given by the British Thyroid Association (BTA) i.e. The clinical consequences of insufficient levels of thyroid hormones in the body”  includes not only the RCP definition, but also those with post thyroid deficiencies, i.e. euthyroid hypometabolism (EHMHM)[13,14] which are recognized by science. Unfortunately, the BTA does not maintain logical consistency with that definition because the association does not embrace post thyroid physiology, diagnostics or therapy. The two definitions for hypothyroidism were believed to be equivalent before 1950, but not after 1970 and the discovery of post thyroid physiology that can adversely affect thyroid hormone levels in the body, namely T3 levels that control the mitochondria.
UKMi: Background first paragraph, third sentence, is incorrect. Liothyronine (T3) has a much shorter half-life (1 day vs.6 days) and steady state levels cannot be maintained with once daily dosing.
UKMis demand for steady state levels of T3 may be misplaced since there are circadian variations. This issue is bogus because the variation is well within the normal range for T3.
This can ONLY be true if there are no post thyroid deficiencies. Unfortunately, post thyroid deficiencies are routinely ignored by Endocrinology, much to the dismay of all those victims of what amounts to medical negligence.
It is not possible to replace natural thyroid extract with synthetic T4 – only, as T4 is a pro-hormone and has little to no effect on its own. Natural thyroid extract contains not only T4, but the active thyroid hormones T3, T2, T1 plus calcitonin.
It is of great concern that a new study Levothyroxine and lung cancer in females; the importance of oxidative stress (published August 2013) shows that there is a correlation between lung cancer and levothyroxine treatment, and oxidative stress caused by T4 supplementation, can be one of the causes.
T4-monotherapy is inadequate for many. It is not an effective treatment for all patients and the UKMi Pharmacists should evaluate ALL available evidence regarding diagnostics and therapy, and the use of the active hormone T3 (either synthetic or natural thyroid extract), for those unable to regain optimal health on T4-monotherapy.[16-92]
The authors of the UKMi Q & A should read the Yellow Card reports that accompany the last 40 plus years of grossly under-reported adverse events on levothyroxine only. They will find no such data for Armour Thyroid, Erfa Thyroid, NatureThroid or Westhroid.
The Medicines and Health Care Regulatory Agency (MHRA} does allow doctors to prescribe the brands Armour Thyroid, Erfa Thyroid, Nature Throid, and Westhroid. These brands of natural thyroid extract are authorised by the FDA as medicines, and are standardised to the specifications of the USP. It is legal to prescribe any one of these brands to a patient in the UK and it can be delivered by UK pharmacies if there is a prescription from a licensed physician.[95,96]
Armour Thyroid, Erfa Thyroid, Nature Throid and Westhroid have never been required to be licensed in the UK. Armour and several other thyroid medications were ‘grandfathered’ in when Congress passed the Kefauver-Harris Drug Efficacy Amendments of 1962 to tighten control over drugs.[97,98] Before marketing a drug; manufacturers had to prove the safety and effectiveness for the product’s intended use. The requirement was applied retrospectively to 1938, when the Food, Drugs and Cosmetics Act was passed. Pre-1938 drugs were allowed because they were generally recognised as safe and effective, provided no evidence to the contrary developed. Too much evidence to the contrary developed concerning levothyroxine products and the FDA decided none was generally recognised as safe and effective, so these synthetic products lost their grandfathered privilege and had to go through the New Drugs Act (NDA) process. These four brands of NDT continue to retain their ‘grandfathered’ status since no evidence to the contrary has developed concerning their safe and effective status.
There is substantial evidence supporting the use of combination therapy, but conventional medical practitioners have made no attempt to evaluate the evidence regarding the use of natural thyroid hormone, and their wholesale dismissal of the concept represents, at least in part, a biased attitude. This biased attitude has been produced by the extensive evidence exclusion philosophy of Evidence-Based Medicine.
The MHRA Review of Unlicensed Medicines makes the point that: Clinicians should have the ability in appropriate circumstances to exercise their professional judgement to commission the supply of an unlicensed medicine to meet the special needs of an individual patient.
UKMi also appear to be ignoring substantial evidence [100-106] showing T4-alone does not work for ALL those suffering symptoms, and doctors have also reported patient dissatisfaction with T4-only therapy.[107-109] Kirk and Kvorning (1947) and Means (1954)  found that not all patients symptoms were mitigated with T4-only.
UKMi has also ignored the existence of numerous subsequent studies on the characteristics of peripheral conversion or metabolism of T4 to T3, and peripheral cellular hormone reception functions [16-92] These patients are NOT suffering with hypothyroidism and need a different diagnosis and therapy protocol. [14,15,109]
The view that hypothyroidism is best treated by T4-only is not, and never has been, based on solid scientific evidence. To this end, the effectiveness of whole thyroid extract versus synthetics should be compared in yet further clinical trials, especially involving problematic patients, as was first shown in a 2007 study comparing levothyroxine and desiccated thyroid extract in hypothyroid patients.
The following studies show that the UKMIs statement that no study has been found that specifically used the Armour Thyroid preparation (and by extension, similar desiccated thyroid products) is clearly FALSE.
There has recently been a new controlled trial, the results of which were published in the May 2013 Journal of Endocrinology by endocrinologists at the Walter Reed National Military Medical Center in Bethesda, Maryland.
There are 12 studies directly comparing natural desiccated thyroid extract to synthetic T4 and T4/T3 combination. Researchers have reported using Armour per se in 3 of these studies [112,114-116] and there are 9 published reports of direct comparison[117-125,] of the two forms of treatment i.e. natural thyroid extract and synthetic thyroxine. There are further studies establishing the clinical benefit of NDT. [126-147] and also reports of the therapeutic equivalence of NDT, T4 and T3. [148-150]
One study, in particular, was published in 1972. The researchers wrote, The present study was designed to compare the effects of desiccated thyroid and mono- sodium l-thyroxine [T4], administered by mouth, on serum lipids in a group of hypothyroid patients. The researchers reported, . . . a cholesterol-lowering effect was manifested by the time of first testing after institution of desiccated thyroid or l-thyroxine treatment. They wrote further, The magnitude of the hypolipidemic (fat lowering) effects, were similar when desiccated thyroid and l-thyroxine were give orally in therapeutic equivalent doses.,p.1047]
Another direct comparison was published in 1978. The researchers wrote, The biologic effect of the two therapies was compared by estimating by interpolation the dose of thyroid hormone that caused the peak serum TSH after TRH to fall to 5 U/ml.[115,p.1518] They concluded, . . . a daily dose of 100 mcg of T4 was on average equal in biologic activity to 100 mg of desiccated thyroid; 60 mg of desiccated thyroid was equal to 60 mcg of T4.[115,p.1518]
Two other research groups showed that the 60mg of desiccated thyroid had the effect of 100mcg of T4 in raising the basal metabolic rate.[147,149] A number of other researchers have made direct comparison of desiccated thyroid and T4.
The primary contention appears to be that if there are no, or not extensive formal trials between these different types of preparations, it is concluded that the synthetic preparations are more efficacious; Please note, there is NO validated published research showing that T4-monotherapy is safe and effective for all sufferers, therefore, the proposition by UKMi that levothyroxine-only therapy works for all patients suffering symptoms of hypothyroidism cannot, and must not be relied upon.
Alternative treatments to synthetic T4 and T3 are supported by decades of research and practice, and synthetic T3 and NDT must not be proscribed for patients with continuing symptoms of hypothyroidism on T4-only therapy. It is ONLY possible to use T4-only if there is no post thyroid deficiency and the peripheral conversion has sufficient extra capacity to handle the extra T4 needed to replace the thyroids production of T3.
The T4-only therapy ignores the need for T3 by those suffering from deficient post thyroid physiology. See The Greater Thyroid System Table.  This table illustrates the flow through this system starting at the top of the chart with signals from the brain to the bottom of the chart where the symptoms are sensed.
The goal of treating patients is mitigation of the symptoms of hypothyroidism, which may co-exist with being chemically euthyroid [13,14,154]
Medicine is quite capable of summarily dismissing evidence, as demonstrated by Sacket who wrote …and if no randomized trial has been carried out for our patients predicament, we must follow the trail to the next best external evidence and work from there,  and worse: If the study wasnt randomized, wed suggest that you stop reading it and go on to the next article. 
The studies found were flawed because:
- they used subjects that did not necessarily have post thyroid deficiencies and consequently had little need for T3,
- the T3-T4 therapies used generally had a lower therapeutic value than the T4 therapy they replaced,
- the analysis techniques used further reduced the impact of low-rate occurrences,
- the conclusion is not supported by the study, because the study did not cover all applications for T3, the methodology was unfair, and the analysis deficient. The recently published paper Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism  takes apart the anti-T3 studies brick by brick. Those studies are about the thyroid gland only.
TPA, having the experience that accords with the test protocol Challenge/De-challenge/Re-challenge (CDR)  is collating a Register of Counterexamples and Triple Counterexamples to T4 Monotherapy, , which shows over 2440 counterexamples (15 October 2013). This Register records patients who continued to suffer symptoms on T4-only, yet found these symptoms were mitigated or remitted when they began T3 hormone therapy. The lack of counterexamples is the best evidence of good science.
The TPA Register has over double the number of participants in the studies showing that T4/T3 combination therapy worked no better than T4-only therapy (1216 participants)
The proscription of all T3-containing therapies has many such patient counterexamples. The evidence gathered by TPA alone indicates that Endocrinologys stance and continuance of T4-only treatment for all those with symptoms of hypothyroidism is without basis and is a pernicious practice causing harm to untold numbers of sufferers.
The Meta-analyses or reviews examine a facet of medicine. These reviews start by searching literature and examining selected literature for subject selection and continue with experimental methods, data analyses, and conclusion. All of these must logically support the current medical guidelines on hypothyroidism. THEY DO NOT.
Please compare the context and the authors conclusion in the abstract. The context is the continuing suffering by those being treated with T4. The conclusion is that T4 should be the only therapy for all sufferers. Is Endocrinology then content to let those, who continue to suffer symptoms onT4-only SUFFER?
The authors of the meta-analysis conclusion are then, understandable, after having summarily dismissed evidence using the EBM philosophy of excluding evidence. However, such dismissal does not comport with legal evidence exclusion. The dismissal of relevant literature and the studies scope, that is limited to the thyroid gland, renders the analysis and conclusions nonsensical.
An important factor in the design of studies is the choice of subjects, and the comparison. Since these studies are not representative of those with deficient peripheral metabolisms or increased peripheral hormone receptor resistance, THEY ARE DEFECTIVE.
The literature searches taken by three meta-analyses,[158-160] considered only 11, 9, and 9 studies respectively out of the 501 that were relevant. They rejected 490 of these studies. Thus, the investigations were reduced by 98% just because they were not done via RCTs.
Among the studies not considered were:
- Post-thyroid physiology [161-163]
- Warnings that T4-only therapy failed to mitigate the symptoms of hypothyroidism in some patients
- Verification of euthyroid hypometabolism, finding symptoms similar to hypothyroidism, and consequential production of patient counterexamples 
- Studies disagreeing with the meta-analyses conclusions [164,165]
- T3 being more active than T4, which suggests the meta-analyses examined a special situation, subjects whose post-thyroid physiology was not deficient; and
- Study and proper treatment of patients failed by endocrinology, finding symptoms similar to hypothyroidism, and consequential production of patient counterexamples.
The dismissal of applicable literature renders the analysis and conclusions of the meta-analyses so overstated they are false.
The focus on the thyroid gland suggests, in the literature, a 14 to 1 exchange because that is the ratio of T4 to T3 in the thyroid gland. Some studies used other ratios, such as 10:1 or 5:1. However, according to Celi, the relative therapeutic value is 3:1, indicating that those on the T4/T3 combination were under-treated. Furthermore, the T3 dosage levels were generally below the starting dose for adults. Moreover, the statistical averaging makes any improvement appear negligible.
These studies, which UKMi have used to back up statements in their Q&As report, should now be acknowledged as woefully deficient and discounted.
Armour Thyroid does have a higher amount of T3 compared to T4 than the relative amounts of T3 to T4 secreted by the human thyroid gland, however it is well documented that natural thyroid extract is often more effective and is better tolerated than synthetic preparations of T4, T3 and T4/T3 combination.[169,170] This is because the T3 in natural thyroid extract is absorbed more slowly than synthetic (purified, unbound) T3. It is also recommended that patients split their dose of NDT (and synthetic T3) into 2 or 3 doses daily to avoid such adverse reactions. Since T3 has a half-life or exponential decay, this can be mathematically analysed. This analysis shows that by taking T3 three times daily produces a variation far less than the normal range and potentially as low as the normal rhythms of the body. See Analysis 1- Exponential Decay 
The point of thyroidologists may be to titrate T4 until TSH is within the normal range. The point of medicine is to relieve patients of their adverse symptoms. This requires a deeper examination of physiology. The hypothalamus-pituitary-thyroid axis is nearly half of the relevant physiology. The remainder falls outside of the classical endocrine system and includes the:
- peripheral metabolism of T4 to T3,
- cellular hormone receptors for T3,
- T3 control of mitochondrial conversion of blood sugar and oxygen to water, carbon dioxide, and energy, and
- clearance of hormones into urine and faeces.
Unfortunately, this physiology does not offer as many tests. The measurements are serum T3 or free T3, hormones in the urine, the resting or basal use of oxygen, which indicates energy production, and resting or basal body temperature, preferably under controlled conditions. Without doing these tests, the healthcare professional has no idea why a patient has continuing symptoms when the thyroid tests are “normal.”
Also, by the logic that underpins the differential diagnostic protocol, these tests must be done to properly diagnose patients with continuing symptoms. In other words, endocrinology has been myopic in its diagnosis and treatment of the symptoms of hypothyroidism. This medical inadequacy is demonstrated by the numerous patient counterexamples whose lives have been virtually resurrected by addressing this additional physiology and replacing T3, its operative hormone,
A prominent endocrinologist claimed the following in a 2005 Food and Drug Administration meeting: T3 is the active ingredient, and its the thing that accounts for the thyroid hormone action. As Ive been reminded many times, there are no intracellular events that we know that can be described by T4 at the level of the nucleus. Only T3. T4 is not the active compound. Likewise, the site of action is in the nucleus.
Obviously, with the dismissal of post-thyroid assays, NHS healthcare professionals attempting to care for patients with continuing symptoms of hypothyroidism do not have sufficient information. It is sincerely hoped therefore, that UKMi Pharmacists will revise their Questions and Answers regarding What is the rationale for using a combination of levothyroxine and liothyronine (such as Armour Thyroid) to treat hypothyroidism? based on a careful reading of the original reports of the studies to which they refer and taking note of the findings described above. This lack of information makes the existence of counterexamples to T4-only therapy reasonable.
1. Saravanan P, Chau F, Roberts N, et al: Psychologi*!”$%^&*cal well-being in patients on adequate doses of L-thyroxine. Results of a large, controlled community-based questionnaire study. Clin Endocrinol, 2002; 57: 577-5852. P Saravanan, C M Dayan, Integrative Neuroscience and Endocrinology, University of Bristol ‘Understanding Thyroid Hormone Action and the Effects of Thyroid Hormone Replacement Just the Beginning Not the End’: http://www.hotthyroidology.com/editorial_135.html3. CHOPRA IJ: Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82: 329-334, 1997.4. Gross J, Pitt-Rivers R. 3:5:3′-triiodothyronine. 2. Physiological activity. Biochem J. 1953 Mar;53(4):652-75. Joint Committee on Higher Medical Training, Higher Medical Training Curriculum for Endocrinology and Diabetes Mellitus, 20036. GMC SPECIALTY TRAINING CURRICULUM FOR ENDOCRINOLOGY AND DIABETES MELLITUS AUGUST 2010 (AMENDMENTS AUGUST 2012). Joint Royal Colleges of Physicians Training Board. http://www.gmc-uk.org/Endocrinology_Diabetes_Curriculum_AMENDMENTS_AUG_2012_081012_V0.pdf_50330155.pdf7. Map of Medicine: Royal College of Physicians Joint specialty societies. http://eng.mapofmedicine.com/evidence/map/thyroid_disorders1.html8. Lowe, John. Thyroid Hormone Replacement Therapies: Ineffective and Harmful for Many Hypothyroid Patients. May 4, 2004 http://www.drlowe.com/frf/t4replacement/intro.htm9. Pritchard EK, The Linguistic Etiologies of Thyroxine-Resistant Hypothyroidism, Thyroid Science www.thyroidscience.com click on debate.10. Pritchard Eric MSc. Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism. Journal of Orthomolecular Medicine Volume 28, Number 2, 201311. The Royal College of Physicians http://www.rcplondon.ac.uk/sites/default/files/the-diagnosis-and-management-of-primary-hypothyroidism-revised-statement-14-june-2011_2.pdf12. The British Thyroid Association website patient information at www.british-thyroid-association.org/info-for-patients/13. Goldberg M, The Case For Euthyroid Hypometabolism, Am J Med Sc October, 1960 pgs 479-4914. Goldberg M, Diagnosis of Euthyroid Hypometabolism, Am J Obst & Gynec, 81(5): 1053-1058, 196115. Umberto Cornelli, Gianni Belcaro, Martino Recchia and Annarosa Finco. Levothyroxine and lung cancer in females: the importance of oxidative stress. Reproductive Biology and Endocrinology 2013, 11:75 doi:10.1186/1477-7827-11-75Published: 8 August 2013 16. OReilly DS. Thyroid function tests-time for a reassessment. BMJ. 2000;320:13324.17. Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, et al. (2011) Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients. PLoS ONE 6(8): e22552. doi:10.1371/journal.pone.002255218. Alley RA, Danowski TS, Robbins T JL, Weir TF, Sabeh G, and Moses CL. Indices during administration of T4 and T3 to euthyroid adults. Metabolism. 1968;17(2):97-10419. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995 Dec;96(6):2828-3820. Asper SP Jr, Selenkow HA, and Plamondon CA. A comparaison of the metabolic activities of 3,5,3-triiodothyronine and l-thyroxine in myxedema. Bull John Hopkins Hosp. 1953; 93: 1621. Blackburn CM, McConahey WM, Keating FR Jr, Albert A. Calorigenic effects of single intravenous doses of l-triiodothyronine and l-thyroxine in myxedematous persons. J Clin Invest. 1954 Jun;33(6):819-2422. Gross J, Pitt-Rivers R. Physiological activity of 3:5:3′-L-triiodothyronine. Lancet. 1952 Mar 22;1(12):593-423. Gross J, Pitt-Rivers R. 3:5:3′-triiodothyronine. 2. Physiological activity. Biochem J. 1953 Mar;53(4):652-724. Burroughs V, Shenkman L. Thyroid function in the elderly. Am J Med Sci. 1982, 283 (1): 8-1725. Carter JN, Eastman CJ, Corcoran JM, and Lazarus L. Inhibition of conversion of thyroxine to triiodothyronine in patients with severe chronic illness. Clin Endocrinol. 1976; 5: 587-9426. Tulp OL and McKee TD Sr. Triiodothyronine neogenesis in lean and obese LA/N-cp rats. Biochem Biophys Res Communications. 1986; 140 (1): 134-427. Katzeff HI, Selgrad C. Impaired peripheral thyroid hormone metabolism in genetic obesity. Endocrinology. 1993; 132 (3): 989-9528. Croxson MS and Ibbertson HK. Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endocrinol Metab. 1977; 44: 167-729. Harns ARC, Fang SH, Vagenakis AG, and Braverman LE. Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat. Metabolism. 1978;27(11):1680-9030. Opstad PK, Falch D, ktedalen O, Fonnum F, and Wergeland R. The thyroid function in young men during prolonged physical exercise and the effect of energy and sleep deprivation. Clin Endocrinol. 1984; 20: 657-6931. Walfish PG. Triiodothyronine and thyroxine interrelationships in health and disease. Can Med Ass. J 1976, 115: 338-32. Feyes D, Hennemann G and Visser TJ. Inhibition of iodothyronine deiodinase by phenolphtalein dyes. Fed Eur Biomed Sci. 1982; 137(1):40-433. Bahn AK, Mills JL, Snyder PJ, Gann PH, Houten L, Bialik O, Hollmann L, and Utiger RD. Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med. 1980; 302: 31-34. Ikeda T, Ito Y, Murakami I, Mokuda O, Tominaga M and Mashiba H. Conversion of T4 to T3 in perfused liver of rats with carbontetrachloride-induced liver injury. Acta Endocrinol. 1986;112: 89-9235. Paier, B; Hagmller, K; Noli, MI; Gonzalez Pondal, M; Stiegler, C; Zaninovich, AA. Changes induced by cadmium administration on thyroxine deiodination and sulfhydryl groups in rat liver. J Endocrinol. 1993; 138(2):219-2236. arregrd L, Lindstedt G, Schtz A, Sllsten G. Endocrine function in mercury exposed chloralkali workers. Occup Envir Med. 1994; 51: 536-4037. Burger AG, Lambert M, Cullen M. Interfrence de substances mdicamenteuses dans la conversion de T4 en T3 et rT3 chez lhomme. Ann Endocrinol (Paris). 1981,42:461-938. Grussendorf M, Hfner M. Induction of the thyroxine to triiodothyronine converting enzyme in rat liver by thyroid hormones and analogs. Clin Chim Acta. 1977;80:61-639. Erickson VJ, Cavalieri RR, Rosenberg LL. Thyroxine-5-diodinase of rat thyroid, but not that of liver, is dependent on thyrotropin. Endocrinology. 1982;111:434-440. Rezvani I, DiGeorge AM, Dowshen SA, Bourdony CJ. Action of human growth hormone on extrathyroidal conversion of thyroxine to triiodothyronine in children with hypopituitarism. Pediatr Res. 1981;15:6-941. Schrder-Van der elst JP, Van der heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes. 1992;41:147-5242. Gavin LA, Mahon FA, Moeller M. The mechanism of impaired T3 production from T4 in diabetes. Diabetes. 1981;30:694-943. Hoover PA, Vaughan MK, Little JC, Reiter RJ. N-methyl-D-aspartate does not prevent effects of melatonin on the reproductive and thyroid axes of male Syrian hamsters. J Endocrinology. 1992;133:51-844. Chanoine J-P, Safran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord S, Alex s, Arthur JR, Beckett GJ, Braverman LE, Leonard JL. Selenium deficiency and type II 5-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine. Endocrinology. 1992;130:479-8445. Arthur JR, Nicol F, Beckett GJ. Selenium deficiency, thyroid hormone metabolism, and thyroid hormone deiodinases. Am J Clin Nutr Suppl. 1993; 57:236S-9S46. Beard J, Tobin B, and Green W. Evidence for thyroid hormone deficiency in iron-deficient anemic rats. J Nutr. 1989;772-47. Fujimoto S, Indo Y, Higashi A, Matsuda I, Kashiwabara N, and Nakashima I. Conversion of thyroxine into triiodothyronine in zinc deficient rat liver. J Pediatr Gastroenterol Nutr. 1986;5:799-80548. Olin KI, Walter RM, and Keen CL. Copper deficiency affects selenoglutathione peroxidase and selenodeiodinase activities and antioxidant defense in weanling rats. Am J Clin Nutr 1994;59:654-849. Westgren U, Ahren B, Burger A, Ingemansson S, Melander A. Effects of dexamethasone, desoxycorticosterone, and ACTH on serum concentrations ot thyroxine, 3,5,3-triiodothyronine and 3,3,5-triiodothyronine. Acta Med Scand. 1977;202 (1-2): 89-9250. Heyma P, Larkins RG. Glucocorticoids decrease the conversion of thyroxine into 3,5,3-triiodothyronine by isolated rat renal tubules. Clin Science. 1982; 62: 215-2051. Scammell JG, Shiverick KT, Fregly MJ. Effect of chronic treatment with estrogen and thyroxine, alone and combined, on the rate of deiodination of l-thyroxine to 3,5,3-triiodothyronine in vitro. Pharmacology. 1986;33: 52-752. Aizawa T, Yamada T. Effects of thyroid hormones, antithyroid drugs and iodide on in vitro conversion of thyroxine to triiodothyronine. Clin Exp Pharmacol Physiol. 1981; 8: 215-2553. Voss C, Schrober HC, Hartmann N. Einfluss von Lithium auf die in vitro-Deioderung von l-Thyroxin in der Ratten leber. Acta Biol Med Germ. 1977; 36:1061-554. Hays MT. Absorption of oral thyroxine in man. J Clin Endocrinol Metab. 1968; 28 (6):749-5655. Surks MI, Schodlow AR, Stock Jm, Oppenheimer JH. Determination of iodothyronine absorption and conversion of L-thyroxine using turnover rate techniques. J Clin Invest. 1973; 52:809-1156. Hubbard WK. FDA notice regarding levothyroxine sodium. Federal register. 1997; 62(157): 1-1057. Peran S, Garriga MJ, Morreale de Escobar G, Asuncion M, Peran M. Increase in plasma thyrotropin levels in hypothyroid patients during treatment due to a defect in the commercial preparation . J Clin Endocrinol Metab. 1997;82(10):3192-558. Selivonenko VG, Zaika IV. The function of the thyroid and thyrotropic function in patients with chronic ischemic heart disease and rhythm disorders. Lik Sprava. 1998 Jan-Feb;(1):81-359. Inama G, Furlanello F, Fiorentini F, Braito G, Vergara G, Casana P. Arrhythmogenic implications of non-iatrogenic thyroid dysfunction. G Ital Cardiol. 1989 Apr;19(4):303-10 (Hypothyroidism in patients with hyperkinetic ventricular arrhythmias (25%), atrial fibrillation (37.5%) and atrio-ventricular block (37.5%))60. Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Thyroid function in patients with ventricular arrhythmia. Kardiologiia. 1989 Feb;29(2):64-7 (Hyperthyroidism was diagnosed in 4.8% of 21 patients with persistent ventricular arrhythmias, and latent hypothyroidism was diagnosed in 38.1%)61. Nesher G, Zion MM. Recurrent ventricular tachycardia in hypothyroidism==report of a case and review of the literature. Cardiology. 1988;75(4):301-662. Fredlund BO, Olsson SB. Long QT interval and ventricular tachycardia of “torsade de pointe” type in hypothyroidism. Acta Med Scand. 1983;213(3):231-563. Miura S, Iitaka M, Suzuki S, Fukasawa N, Kitahama S, Kawakami Y, Sakatsume Y, Yamanaka K, Kawasaki S, Kinoshita S, Katayama S, Shibosawa T, Ishii J. Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endocr J. 1996 Dec;43(6):657-664. Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-9265. Telkova IL, Tepliakov AT. Changes of thyroid hormone levels in the progression of coronary artery disease. Arteriosclerosis. Klin Med (Mosk). 2004;82(4):29-3466. Pavlou HN, Kliridis PA, Panagiotopoulos AA, Goritsas CP, Vassilakos PJ. Euthyroid sick syndrome in acute ischemic syndromes. Angiology. 2002 Nov-Dec;53(6):699-70767. Pimenov LT, Leshchinskii LA. Thyroid hormone changes (iodothyroninemia) in patients with acute myocardial infarction, and their clinical significance. Kardiologiia. 1984 Oct;24(10):74-768. Satar S, Seydaoglu G, Avci A, Sebe A, Karcioglu O, Topal M. Prognostic value of thyroid hormone levels in acute myocardial infarction: just an epiphenomenon? Am Heart Hosp J. 2005 Fall;3(4):227-3369. Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33 (namely impairment of systolic ejection, a delay in diastolic relaxation and a decrease in the compliance to the ventricular filling. Several significant correlations were found between the parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis)70. Khaleeli AA, Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinical, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473-671. Reza MJ, Abbasi AS. Congestive cardiomyopathy in hypothyroidism. West J Med. 1975 Sep;123(3):228-372. Rays J, Wajngarten M, Gebara OC, Nussbacher A, Telles RM, Pierri H, Rosano G, Serro-Azul JB. Long-term prognostic value of triiodothyronine concentration in elderly patients with heart failure. Am J Geriatr Cardiol. 2003 Sep-Oct;12(5):293-7 (Lower serum T3 in cardiac failure: the odds ratio for events was 9.8 (95% confidence interval,2.2-43, p=0.004) for patients in the lowest tertile of triiodothyronine, that is, lower than 80 ng/dL, compared with patients with levels above 80 ng/dL73. Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med. 2005 Feb;118(2):132-74. Klein I, Ojama K. In: Werner & Ingbars The Thyroid, ed. Braverman LE & Utiger RD, Lippincott-Raven Publishers, Philadelphia, 1996, 62: 799-80475. Hamilton MA, Stevenson LW, Luu M, Walden JA. Altered thyroid hormone metabolism in advanced heart failure. J Am Coll Cardiol. 1990 Jul;16(1):91-76. Kozdag G, Ural D, Vural A, Agacdiken A, Kahraman G, Sahin T, Ural E, Komsuoglu B. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy. Eur J Heart Fail. 2005 Jan;7(1):113-77. Wortsman J, Premachandra BN, Chopra IJ, Murphy JE. Hypothyroxinemia in cardiac arrest. Arch Intern Med. 1987 Feb;147(2):245-878. Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-1379. Corrective thyroid therapy is safe in hypothyroid patients with common benign cardiac arrhythmias at the condition that thyroid treatment is started at low doses and then gradually and prudently increased to the adequate dose. The treatment does not trigger an increase in arrhythmia frequency except in rare patients with baseline atrial premature beats. It is, however, associated with an increase in basal, average and maximal heart rate80. Polikar R, Feld GK, Dittrich HC, Smith J, Nicod P. Effect of thyroid replacement therapy on the frequency of benign atrial and ventricular arrhythmias. J Am Coll Cardiol. 1989 Oct;14(4):999-100281. Yamauchi K, Takasu N, Ichikawa K, Yamada T, Aizawa T. Effects of long-term treatment with thyroxine on pituitary TSH secretion and heart action in patients with hypothyroidism. Acta Endocrinol (Copenh). 1984 Oct;107(2):218-24 (T4 doses should be adjusted to maintain normal ET/PEP (systolic time intervals) rather than normal serum TSH levels)82. Barnes BO. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancet. 1959 Aug 22;2:149-5283. Holland FW 2nd, Brown PS Jr, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg. 1992 Aug;54(2):301-584. Israel M. An effective therapeutic approach to the control of atherosclerosis illustrating harmlessness of prolonged use of thyroid hormone in coronary disease. Am J Dig Dis. 1955 June;161-885. Yokoyama Y, Novitzky D, Deal MT, Snow TR. Facilitated recovery of cardiac performance by triiodothyronine following a transient ischemic insult. Cardiology. 1992;81(1):34-4586. Perk M, ONeill BJ; The effect of thyroid therapy on angiographic artery disease progression. Can J Card. 1997;13(3):273-687. Zondek H. Myxedema Heart. Munch Med Wochenschr. 1918, 65: 1180-388. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology. 1996 Nov-Dec;87(6):509-1589. Novitzky D, Cooper DK, Chaffin JS, Greer AE, DeBault LE, Zuhdi N. Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation. 1990 Feb;49(2):311-690. Yao J, Eghbali M. Decreased collagen mRNA and regression of cardiac fibrosis in the ventricular myocardium of the tight skin mouse following thyroid hormone treatment. Cardiovasc Res. 1992 Jun;26(6):603-791. Facktor MA, Mayor GH, Nachreiner RF, D’Alecy LG. Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs. Resuscitation. 1993 Oct;26(2):141-692. Shigematsu H, Shatney CH. The effect of triiodothyronine (T3) and reverse triiodothyronine (rT3) on canine hemorrhagic shock. Nippon Geka Gakkai Zasshi. 1988 Oct;89(10):1587-93.93. Medicines and Healthcare Products Regulartory Agency http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con222566.pdf94. Matthews,G. “Armour Thyroid and Porcine Thyroid Extract Replacement Therapy”. . June 29.2004.Medicines and Healthcare Products Regulatory Agency MHRA letter95. IDIS Ltd. Sourcing Unlicensed Named Patients Medicines. .http://www.idispharma.com/showcontent.asp?CollectionID=@0000000004&ParentID=@000000000196. Pharmarama: http://www.pharmarama.com/products/about.asp97. Krantz JC Jr., New Drugs and the Kefauver-Harris Amendment, J New Drugs, 1966, Mar-Apr;6(22):77-9 98. Krantz JC Jr., The Kefauver-Harris amendment after sixteen years, Mil Med. 1978 Dec;143(12):883. 99. Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996 Jun;137(6):2490-50100.Joffe R, Blank DW, Post RM, Uhde TW. Decreased triiodothyronines in depression: A preliminary report. BIOLOGICAL PSYCHI 1985; 20: 922-925.101.Cooke RG, Joffe RT, Levitt AJ. T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. J CLIN PSYCHI 1992; 53, 1 (Jan): 16-18.102.Gelenberg AJ. T3 + T4 = success. BIOLOGICAL THERAPIES IN PSYCHI
[I]NEWS-LTR 1992; 15, 4 (April): 14.[/I]103.Dommisse J. T3 is at least as important as T4 in all hypothyroid patients.J Clin Psychiatry. 1993 Jul;54(7):277-9.104.Whybrow PC (1994): The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Acta Medica Austriaca 21:47-5105.CHOPRA IJ: Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82: 329-334, 1997106.Sjberg S, Eriksson M, Werner S, Bjellerup P, Nordin C. L-thyroxine treatment in primary hypothyroidism does not increase the content of free triiodothyronine in cerebrospinal fluid: a pilot study.Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. email@example.com. Scand J Clin Lab Invest. 2011 Feb;71(1):63-7.107.Leslie J. De Groot. Dangerous Dogmas in Medicine: The Nonthyroidal Illness Syndrome. The Journal of Clinical Endocrinology & Metabolism January 1, 1999 vol. 84 no. 1 151-164108.Dr. E. Chester Ridgway, Director of Endocrinology at the University of Colorado Health Sciences Center, Equivalence of Levothyroxine Sodium Products, Joint Public Meeting (Cosponsored with the American Thyroid Association, The Endocrine Society, and the American Association of Clinical Endocrinologists) Monday, May 23, 2005, pages 144-11 145 109.Baisier, WV, Hertoghe, J., B, Eekhaut, W., Thyroid Insufficiency? Is Thyroxine the Only Valuable Drug?, Journal of Nutritional and Environmental Medicine, Vol. 11, No. 3, September 2001, pages 159-166110.Means JH: Lectures on the thyroid. Cambridge, MA. Harvard University Press. 1954; 48-49111.Kirk E, Kvorning SA, Acta Med. Scandinav., Suppl. 184. pp 3-83. 1947112.Gautam Das, Shweta Anand & Parijat De. Diabetes and Endocrione Unit, City Hospital,Birmingham, United Kingdom Does synthetic thyroid extract work for everybody? Endocrine Abstracts (2007) P316113.Thanh D. Hoang, Cara H. Olsen, Vinh Q. Mai, Patrick W. Clyde, and Mohamed K. M. Shakir.Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study JCEM 2013 98: 1982-1990114.Singh, S.P., Feldman, E.B., and Carter, A.C.: Desiccated thyroid and levothyroxine in hypothyroidism: comparison in replacement therapy. N.Y. State J. Med., 72(9):1045-1048, 1972.115.Sawin, C.T., Hershman, J.M., Fernandez-Garcia, R., et al.: A comparison of thyroxine and desiccated thyroid in patients with primary hypothyroidism. Metabolism, 27(10):1518-1525, 1978.116.LeBoff, M.S., Kaplan, M.M., Silva, J.E., et al.: Bioavailability of thyroid hormones from oral replacement preparations. Metabolism, 31(9):900-905, 1982.117.Lavietes, P.H.. and Epstein, F.H.: Thyroid therapy of myxedema: A comparison of various agents with a note on thecomposition of thyroid secretion in man. Ann. Intern. Med., 60:79-87, 1964.118.Gorowski, T., Pucilowska, J., and Wernic, K.: Comparative effects of desiccated thyroid gland and sodium salt of L-thyroxine in the treatment of hypothyroidism.Pol. Tyg. Lek., 44(32-33):768-770, 1989.119.Felt, V. and Nedvidkova, J.: Comparison of treatment with L-thyroxine and a dried thyroidgland preparation in patients with hypothyroidism. Vnitr. Lek., 28 (11):1067-1073, 1982120.Wartofsky, L.: Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: are we a step closer to the magic formula? Thyroid, 14(4):247- 248, 2004121.Kosowicz, J., Horst-Sikorska, W., Lacka, K., et al.: Outcome of treating hypothyroidism with thyreoideum. Pol. Tyg. Lek, 48(27-28):599-602, 1993.122.Warszawie, C.M.K.P.: Treatment of hypothyroidism with L-thyroxine. Pol. Tyg. Lek, 48(27-28):605-608, 1993.123.McGavack, T.H. and Reckendorf, H.K.: Therapeutic activity of desiccated thyroid substance, sodium Lthyroxine and D, L-triiodothyronine: a comparative study. Am. J. Med., 20:774-777, 1956124.Baisier, W.V., Hertoghe, J., and Eeckhaut, W.:Thyroidinsufficiency: is thyroxine the only valuable Drug? J. Nutr. Environ. Med., 11:159-166, 2001.125.Alan R. Gaby, MD. Sub-laboratory Hypothyroidism and the Empirical use of Armour Thyroid. (Altern Med Rev 2004;9(2):157-179)126.Lowe, J.C.: Natural desiccated thyroid: Guttlers false claim about It. Thyroid Science 4(9):C1-6, 2009127.Novak, Edmund A. M.D.; Holthaus, Joseph M. M.D.; Ogborn, Richard O. M.D: Clinical Study of Levo-Thyroxine and Aged Desiccated Thyroid in Euthyroid Subjects: American Journal of the Medical Sciences: March 1964128.Alan R. Gaby, MD. Sub-laboratory Hypothyroidism and the Empirical use of Armour Thyroid. (Altern Med Rev 2004;9(2):157-179)129.Thompson, W.O., McLellan, L.L., Thompson, P.K., et al.: The rates of utilization of thyroxine and of desiccated thyroid in man: the relation between the iodine in desiccated thyroid and thyroxine. Arch. Intern. Med., 1932.130.Boothby, W. M., Sandiford, I., Sandiford, K., et al.: Abstract of Communication to the XIIth International Physiol. Congress held at Stockholm, Aug. 3-6, 1926. Skandinav. Archiv. 1926, xlix, 99. Metabolism studies showing the effect of desiccated thyroid and thyroxin on a patient with myxedema.131.Thompson, W.O., Nadler, S.B., Taylor, S. G., III, and Thompson, P. K.: The calorigenic action of various thyroid derivatives. J. Clin. Invest. (Proc.), 13:690, 1934.132.Foster, G. L., Palmer, W. W., and Leland, J. P.: A comparison of the calorigenic potencies of l-thyroxine, dl-thyroxine, and thyroid gland, with a note on the thyroxine content of the acid-soluble fraction of the peptic digest of thyroid protein. J. Biol. Chem., 115:467, 1936133.Thompson, W. O., Thompson, P. K., Brailey, A. G., et al.: The calorigenetic action of thyroxin at different levels of basal metabolism in myxedema. J. Clin. Invest., 7(3): 437463, 1929.134.Sturnick, M.I. and Falcon-Lesses, M.: A comparison of the effect of desiccated thyroid and sodium levothyroxine on the serum protein-bound iodine. New Engl. J. Med., 264:609, 1961.135.Sisson, J.C.: Principles of, and pitfalls in, thyroid function tests. J. Nuclear Med., 6:853-901, 1965.136.Robertson, J.D. and Kirkpatrick, H.F.W.: Changes in basal metabolism, serum protein-bound iodine and cholesterol during treatment of hypothyroidism with oral thyroid and l-thyroxine sodium. Brit. Med. J., March 22, 1:624, 1952.137.Gilman, A.G. and Murad, F.: Thyroid and antithyroid drugs. In The Pharmacologic Basis of Therapeutics, (ed 5). Edited by L.S. Goodman and a. Gilman, New York, MacMilIan, 1975, p.1398.138.Means, J.H., DeGroot, L.J., and Stanbury, J.B.: The Thyroid and Its Diseases, 3rd edition. New York, McGraw-Hill, 1963, p. 334.139.Werner, S.C.: Treatment of hypothyroidism. In The Thyroid, 3rd edition. Edited by S.C. Werner and S.H. Ingbar, New York, Harper and Row, 1971, p.834.140.Daughaday, W.H.: The adenohypophysis. In Textbook of Endocrinology, 5th edition. Edited by R.H. Williams, Philadelphia, Saunders, 1974, p.60.141.Lowe, J.C.: Stability, effectiveness, and safety of desiccated thyroid vs levothyroxine: rebuttal to the British Thyroid Association. Thyroid Science, 4(3):C-1-12, 2009.142.Novak, Edmund A. M.D.; Holthaus, Joseph M. M.D.; Ogborn, Richard O. M.D: Clinical Study of Levo-Thyroxine and Aged Desiccated Thyroid in Euthyroid Subjects: American Journal of the Medical Sciences: March 1964143.Frederick L. Benoit.ieutenant Commander, MC, MC, USN: Treatment of Riedel’s Thyroiditis With Desiccated Thyroid.Endocrine Clinic and Medical Service, U.S. Naval Hospital,Oakland..Submitted July 14, 1964.144.Beverley Strisower, A.B.,John W Gofman, MD., Elmer Galioni, MD.,Joshua H Rubinger, M.D.,Georgfe W OBrien M.D. and Alexander Simon, M.D. Effect of Long-Term Administration of Desiccated Thyroid on Serum Lipoprotein and Cholesterol Levels.The Journal of Clinical Endocrinology & Metabolism January 1, 1955 vol. 15 no. 1 73-80145.George S. Serif and Alan K Brevik.: ” Effects of Butyl-4-hydroxy-3,5-diiodobenzoate on the Conversion of p-carotene to Vitamin A in the Rat.” The Journal of Biological Chemistry. Vol. 235, No. 8, August 1960146.McGavack, T. R. and Reckendorf, H. K.: Therapeutic activity of desiccated thyroid substance, sodium Ithyroxine and d,1 triiodothyronine: A comparative study. Amer. J. Med., 20: 774, 1956.147.Singh, S.P., Feldman, E.B., and Carter, A.C.: Desiccated thyroid and levothyroxine in hypothyroidism: comparison in replacement therapy. N.Y. State J. Med., 72(9):1045-1048, 1972.148.Lavietes, P.H. and Epstein, F.H.: Thyroid therapy of myxedema: A comparison of various agents with a note on the composition of thyroid secretion in man. Ann. Intern. Med., 60:79-87, 1964.149.Haynes, R.C., Jr.: Thyroid and antithyroid drugs. In Goodman and Gilmans The Pharmacological Basis of Therapeutics, 8th edition. New York, Pergamon Press, 1990, pp.1361-1383.150.U.S. Food and Drug Administration. Guidance for industry. Postmarketing safety reporting for human drug and biological products including vaccines. Retrieved from: [www.fda.gov/downloads/Biolog*!”$%^&*icsBloodVaccines/GuidanceComplianceRegulatoryIn*!”$%^&*formation/Guidances/Vaccines/ucm092257.pdf].151.Pritchard E. The Greater Thyroid System Table http://tpauk.com/articles/2667-the-greater-thyroid-system-table/152.Sackett, DL, Rosenberg MC, Muir Gray JA, et al: Evidence Base Medicine: What it is and what it isnt. BMJ, 1996; 312: 71-72.153.Sackett, DL, Straus, SE, Richardson WS, et al: Evidence-based medicine: how to practice and teach EBM. 2nd edition. Edinburgh, UK. Churchill Livingstone. 2000.154.Baisier WV, Hertoghe J, Beekhaut W: Thyroid in*!”$%^&*sufficiency? Is thyroxine the only valuable drug? J Nutr Environ Med, 2001; 11: 159-166.155.Rippere V. Biochemical victims: False negative diagnosis through overreliance on laboratory resultsa personal report. Med Hypotheses. 1983; 10(2): 113156.Turner S. Register of Counterexamples to T4-Monotherapyhttp://tpauk.com/articles/3114-world-register-of-counterexamples-and-triple-counterexamples-to-t4-only-therapy/157.Popper KR: Conjectures and Refutations. The Growth of Scientific Knowledge. New York, NY. Routledge Classics. 2003; 43-51158.Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al: Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothy*!”$%^&*roidism: meta-analysis of randomized controlled trials. J Clin Endocrin Metab, 2006; 91: 2592-2599.159.Joffe RT, Brimacombe M, Levitt AJ, et al: Treat*!”$%^&*ment of clinical hypothyroidism with thyroxine and triiodothyronine: a literature review and meta-analysis. Psychomatics, 2007; 48: 379-384160.Escobar-Morreale H, Botella-Carretero JI, Escobar del Rey F, et al: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine, J Clin Endocrinol Met, 2005; 90: 4946-4954.161.Refetoff S, Dewind LT, DeGroot LJ, et al: Syn*!”$%^&*drome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refactoriness to thyroid hormone. J Clin En*!”$%^&*docrinol Metab, 1967; 27: 279-294.162.Braverman LE, Ingbar SH, Keinwem S: Conver*!”$%^&*sion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin Invest, 1970; 49: 855-864.163.Wrutniak-Cabello C, Casas F, Cabello G: Thyroid hormone action in mitochondria. J Molec Endocrin, 2001; 26: 67-77.164.Goldberg M: The case for euthyroid hypometabo*!”$%^&*lism. Am J Med Sci, 1960; 240: 479-493.165.Taylor S, Kapur M, Adie R: Combined thyroxine and triiodothyronine for thyroid replacement ther*!”$%^&*apy. BMJ, 1970; 2: 270-271.166.Gullo D, Latina A, Frasca F, et al: Levothyrox*!”$%^&*ine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One, 2011: 6(8): e22552. 167.Gross J, Pitt-Rivers R: 3: 5: 3-Triiodothyronine Physiological Activity. Biochem J, 1953; 53: 652-657168.Celi FS, Zemskova M, Linderman JD, et al: The pharmacodynamic equivalence of levothyroxine and liothyronine. A randomized, double-blind, cross-over study in thyroidectomized patients. Clin Endocrinol, 2010; 72: 709-715.169.Steven L. Richheimer, Charlotte B. Jensen. Response to Liothyronine and Levothyroxine in Armour Thyroid?: 1987.Journal of Pharmaceutical Sciences. Volume 76, Issue 4. Pages 346-347170.Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism. 1977 Nov;26(11):1213-8171.Alan R. Gaby, MD Alternative Medicine Review Volume 9, Number 2, 2004