Charles Matthews M.D.
Director, the North Carolina Comprehensive Headache Clinic
Thyroid Protocol: Thyroid Augmentation for Refractory Headache
Thyroid Protocol: Thyroid Augmentation for Refractory Headache
Prior to 1980, when the protein bound iodine test for thyroid status was introduced, the assessment of thyroid function utilized clinical criteria and, when available, determination of basal metabolic rate (1). At that time dessicated thyroid preparations were commonly administered for a variety of functional disorders (2). The definition of hypothyroidism historically shifted from the physical examination and became based on normative data for the TSH, but was never correlated with the previously accepted clinical criteria for hypothyroidism and clinical practice in the use of thyroid supplementation (3). The sole reliance on blood tests for defining thyroid function has met with controversy is recent years, some of which is directed at the question of optimum rather than normal TSH, and some of which questions the status of the TSH itself when clinical markers diverge (4).
Migraine and thyroid:
Migraine is a systemic disease involving the brain, as well as the autonomic, cardiovascular, endocrine, gastrointestinal, and immune systems (5). In addition to the manifestations of head pain, there is a substantial overlap between chronic headache and other functional disorders, such as chronic fatigue, weight gain, irritable bowel syndrome, mood disorders, sleep disturbance, fibromyalgia, and menstrual irregularities. The overlap between headache and each functional disorder reaches 70% in the refractory headache population, raising the question of whether these conditions have entirely distinct etiologies (6). Many patients presenting at headache clinics are on multiple medications of the antidepressant, anticonvulsant, and antihypertensive classes, often with side effects which exacerbate one of the other functional disorders (common examples include weight gain and fatigue with antidepressants, depression with beta blockers, constipation and exacerbation of IBS with tricyclics, and menstrual irregularities and precipitation of PCOS with anticonvulsant medication.
Migraine may appear as a slowly traveling cortical metabolic defect called the Spreading Depression of Leao on functional imaging. The etiology of this metabolic defect is unknown, but may be a manifestation of mitochondrial dysfunction (7). Migraine has been linked with mitochondrial disorders; the evidence is strongest in migraine with aura and hemiplegic migraine (8). Some known mitochondrial abnormalities cause migraine (for example, MELAS). Ubiquinone, a mitochondrial co-factor, has been used successfully to treat migraine in limited clinical trials (9). Migraine is associated with hypocapnia in the presence of elevated serum lactate and other Krebs Cycle acids, , suggesting respiratory compensation for an underlying metabolic acidosis, possibly explained by a diffuse mitochondrial dysfunction; migraine is also associated with interictal and ictal hypothermia(10).
Mitochondrial output and number, and by extension basal body temperature and CO2 production, are under the primary control of the thyroid gland. It has been demonstrated that environmental agents such as insecticides, processed fats, plasticizers, and food additives interfere with the effect of thyroid on mitochondria (12). It has been speculated that this effect may be passed up through the food chain and concentrated ("biological lensing") causing endocrine disruption in humans (13). It is likely that environmental endocrine disruptors, as well as individual variability in central nervous system local uptake and utilization of liothyronine, plays a role in the development of migraine, even in patients with normal laboratory functions.
Experience to date:
There are multiple anecdotal references to the successful treatment of migraine with thyroid augmentation prior to 1980, and one published trial of 100 patients with headache reporting 95 responders and no significant side effects (14). At that time, dessicated (whole) thyroid was used, which contains T4, T3, T2, calcitonin, and selenium. No negative studies were published to account for the lapse of the use of thyroid augmentation for headache, and the practice of thyroid supplementation declined as the more narrow definition of hypothyroidism became adopted with the advent of the TSH and the popularity of synthetic L-thyroxine (T4) as sole therapy for hypothyroidism.
In an initial series of fifty patients referred to the Headache Clinic, refractory to multiple medications and other therapeutic modalities, thyroid augmentation appears to be effective in relieving symptoms of headache, and in many instances, of multiple other functional disorders, as well as correcting hypocapnia and basal hypothermia. Thyroid augmentation appears to be well tolerated. Other practitioners have described similar positive experiences (Marcelo Bigal M.D., Ray Peat Ph.D., Broda Barnes foundation members, the Belgian endocrinologist Thierry Hertzoghe M.D., personal communications).
Endocrinologists have extensive clinical experience in thyroid augmentation (TSH suppression) for thyroid cancer, and there is a long tradition in psychiatry in treating refractory depression with thyroid augmentation. The combined clinical experience suggests that thyroid augmentation, and TSH suppression, is well tolerated (15). Recent studies further support the safety of maintaining higher thyroid hormone levels (and a low TSH) as a therapeutic option (16)(17).
Standards of Care Concerns:
During thyroid augmentation, TSH is expected to fall to "hyperthyroid" levels and may become undetectable. Except for management of thyroid cancer, and for treatment of certain types of depression, maintaining a low or undetectable TSH for therapeutic purposes in treating headache is not a current standard of care.
Excess thyroid administration may be associated with cardiac arrhythmias, myocardial infarction, anxiety or panic attacks, and weight loss. Some, but not all, authors raise concerns about osteoporosis. Suppression of endogenous thyroid function may occur. There is insufficient information on the practical relevance of such risks under supervised thyroid augmentation for headache, and there may be side effects which are not presently known. These potential risks will be monitored carefully, and must be balanced against the risks of lack of treatment and of their current treatment. Since thyroid augmentation increases the clearance of cortisol, in patients with adrenal compromise, thyroid augmentation may precipitate symptoms of adrenal insufficiency.
1) Thyroid Diseases: Basic Science, Pathology, Clinical and Laboratory Diagnoses by Luigi Troncone, Brahm Shapiro, Maria A. Satta, and Fabrizio Monaco
2) Hypothyroidism: The Unsuspected Illness by Broda Barnes M.D. Ph.D.
This book was written by a clinician and researcher during the active years of thyroid supplementation and contains extensive information on his years of clinical experience in thyroid augmentation.
3) Raymond Peat Ph.D. in "Thyroid Therapy" article posted on Raypeat.com.
Ray Peat is an endocrine physiologist who has written a number of books and articles which are conveniently posted on his web site.
4) This viewpoint and literature is summarized in this article posted on thyroid.com, a patient advocate site.
The TSH Reference Wars: What's "Normal?", Who is Wrong, Who is Right...And What does it all Mean for You and Your Health? by Mary Shomon
2) Hypothyroidism: The Unsuspected Illness by Broda Barnes M.D. PhD.
This article discusses migraine from a systemic disease point of view.
6) Cole JA, Rothman KJ, Cabral HJ, Zhang Y, Farraye FA (2006). "Migraine, fibromyalgia, and depression among people with IBS: a prevalence study". BMC gastroenterology 6: 26. doi:10.1186/1471-230X-6-26. PMID 17007634.
7) "Mechanisms of migraine aura revealed by functional MRI in human visual cortex", Hadjikhani et al., PNAS 98 (2001), pages 4687-4692
8) Mitochondrial dysfunction and migraine: evidence and hypotheses.
Cephalalgia. 26(4):361-372, April 2006.
Sparaco, M 1; Feleppa, M 1; Lipton, R B 2,3,4; Rapoport, A M 5,6; Bigal, M E
9) Open label trial of coenzyme Q10 as a migraine preventive.
TD Rozen, ML Oshinsky, CA Gebeline, KC
Cephalalgia:Volume 22(2)March 2002p 137-141
10) Personal observation unpublished data
11) Studies on the rapid stimulation of mitochondrial respiration by thyroid hormones. O'Reilly and Murphy. Acta Endocrinologica, Vol 127, Issue 6, 542-546
12) Unsaturated Vegetable Oils: Toxic. An article posted by Ray Peat Ph.D. at
14) Hypothyroidism: the Unsuspected Illness by Broda Barnes M.D. Ph.D.
15) Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. Howland, R H J-Clin-Psychiatry. 1993 Feb; 54(2):47-54
16) Leese, Graham & Flynn, Robert. "Is it safe for patients taking thyroxine to have a low but not suppressed serumTSH concentration?," Endocrine Abstracts (2010) 21 OC5.6, Society for Endocrinology BES 2010, 15 March 2010 - 18 March 2010, British Endocrine Societies. Online
17) "Low TSH levels may be safe for patients taking thyroxine replacement." Endocrine Today. Posted on March 22, 2010, Online
Thyroid hormone utilization requires enzyme participation, and recent work on deiodinase polymorphisms reflect a rapidly emerging understanding of the potential role of brain thyroid utilization in the genesis of common functional disorders such as chronic pain, depression, and fatigue.
1. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases Endocrine Reviews 2002;23 (1):38-89.
2. Silva JE, Larsen PR. Pituitary nuclear 3,5,3_-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science 1977;198:617–620
3. Koenig RJ, Leonard JL, Senator D, Rappaport N, Regulation of thyroxine 5’-deiodinase activity by 3,5,3’-triiodothyronine in cultured rat anterior pituitary cells. Endocrinology 1984;115(1):324-329.
4. Silva JE, Dick TE, Larsen PR. The contribution of local tissue thyroxine monodeiodination to the nuclear 3,5,3’-triiodothyroinine in pituitary, liver and kidney of euthyroid rats. Endocrinology 1978;103:1196. location of D2
5. Visser TJ, Kaplau MM, Leonard JL, Larsen PR. Evidence for two pathways of iodothyroinine 5’-deiodination in rat pituitary that differ I kinetics, propylthiouracil sensitivity, and response to hypothyroidism. J Clin Invest 1983;71:992.
6. Larsen PR, Silva JE, Kaplan MM. Relationship between circulation and intracellular thyroid haomrones: physiological and clinical implications Endcor Rev 1981;2:87.
7. Kaplan MM. The Role of Thyroid Hormone Deiodination in the Regulation of Hypothalamo-Pituitary Function Progress in Neuroendocrinology. Neuroendocrinology 1984;38:254-260.
8. Peeters RP, Geyten SV, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;12:6498–507.
9. Peeters RP, Wouters PJ, Toor HV, et al. Serum 3,3_,5_-Triiodothyronine (rT3) and 3,5,3_-Triiodothyronine/rT3 Are Prognostic Markers in Critically Ill Patients and Are Associated with Postmortem Tissue Deiodinase Activities. J Clin Endocrinol Metab 2005;90(8):4559–4565.
10. Campos-Barros A, Hoell T, Musa A, Sampaolo S, et al. Phenolic and tyrosyl ring iodothyronine deiodination and thyroid hormone concentrations in the human central nervous system. J Clin Endocrinol Metab 1996; 81:2179–2185.
11. Chopra IJ, Chopra U, Smith SR, et al. Reciprocal changes in serum concentrations of 3,3’,5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 1975;41:1043–9.
12. Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3_,5_- triiodothyronine (reverse T3) and 3,3_,5-triiodothyronine (T3). J Clin Endocrinol Metab 1975;41:911–920.
13. Duick DS, Warren DW, Nicoloff JT, Otis CL, Croxson MS. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 1974;39:1151-1154.
14. Cavalieri RR, Castle JN, McMahon FA. Effects of dexamethasone on kinetics and distribution of triiodothyronine in the rat. Endocrinology 1984;114:215–221.
15. Bianco AC, Nunes MT, Hell NS, Maciel RMB. The Role of Glucocorticoids in the Stress-Induced Reduction of Extrathyroidal 3,5,3′-Triiodothyronine Generation in Rats Endocrinology 1987 120: 1033-1038,
16. DeGroot LJ. Non-thyroidal illness syndrome is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge. J Endocrinol Invest 2003;26:1163-1170.
17. Reed HL, Brice D, Shakir KM, Burman KD, et al. Decreased free fraction of thyroid hormones after prolonged Antarctic residence. J Applied Physiol 1990;69:1467-1472.
18. Forhead AJ, Curtis K, Kaptein E, Visser TJ, Fowden Al. Developmental Control of Iodothyronine Deiodinases by Cortisol in the Ovine Fetus and Placenta Near Term. Endocrinology 2006;147:5988-5994
19. Nicoloff JT, Fisher DA, Appleman MD. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest. 1970; 49(10): 1922–1929.
20. Brabant G, Brabant A, Ranft U, Ocran K et al. Circadian and Pulsatile Thyrotropin Secretion in Euthyroid Man Under the Influence of Thyroid Hormone and Glucocorticoid Administration J Clin Endocrinol Metab .1987; 65: 83-88.
21. Benker G, Raida M, Olbricht T. et al. TSH Secretion In Cushing’s Syndrome: Relation To Glucocorticoid Excess, Diabetes, Goitre, And The ‘Sick Euthyroid Syndrome’. Clin Endocrinol 1990;33(6):777-86.
22. Mebis L, Langouche L, Visser TJ, Van den Berghe G. The type II iodothyronine is up-regulated in skeletal muscle during prolonged critical illness. J Endocrinol Metab 2007;92(8):3330-3333.
23. Linnoila M, Lamberg BA, Potter WZ, Gold PW, Goodwin FK. High reverse T3 levels in manic and unipolar depressed women. Psychiatry Research 1982;6:271-276.
24. Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L. Reverse T3 levels in affective disorders. Psychiatry Research 1983;10:1-9.
25. Jackson I. The thyroid axis and depression. Thyroid 1998;8(10):951-956.
26. Gitlin M, Altshuler LL, Frye MA, Suri M, Huynh EL, et al. Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors. J Psychiatry Neurosci 2004;29(5):383-386.
27. Clausen P, Mersebach H, Nielsen B, et al. Hypothyroidism is associated with signs of endothelial dysfunction despite 1-year replacement therapy with levothyroxine. Clinical Endocrinology 2009;70:932–937.
28. Duval F, Mokrani MC, Bailey P, Correa H, et al. Thyroid axis activity and serotonin function major depressive episode. Psychoneuroendocrinology 1999;24:695-712.
29. Unden F, Ljunggren JG, Kjellman BF, Beck-Friis J, Wetterberg L. Twenty-four-hour serum levels of T4 and T3 in relation to decreased TSH serum levels and decreased TSH response to TRH in affective disorders. Acta Psychiatr Scand 1986;73:358-365.
30. Linnoila M, Lamberg BA, Rosberg G, Karonen SL, Welin MG. Thyroid hormones and TSH, prolactin and LH responses to repeated TRH and LRH injections in depressed patients. Acta Psychiat Scand 1979;59:536-544.
31. Kirkegaard C, Faber J. Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression. Acta Endocrinologica 1981;96:199-207.
32. Sintzel F, Mallaret M, Bougerol T. Potentializing of tricyclics and serotoninergics by thyroid hormones in resistant depressive disorders. Encephale 2004;30(3):267-75.
33. Panicker V, Evans J, Bjoro T, Asvold BO. A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the Hunt study. Clinical Endocrinology 2009;71:574-580.
34. Thompson FK. Is there a thyroid-cortisol-depression axis? Thyroid Science 2007;2(10):1.
35. Forman-Hoffman V, Philibert RA. Lower TSH and higher T4 levels are associated with current depressive syndrome in young adults. Acta Psychiatry Scand 2006;114:132-139.
36. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in biolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry 2002; 159:116–121.
37. Premachandra1 BN, Kabir MA, Williams IK. Low T3 syndrome in psychiatric depression. J Endocrinol Invest 2006;29: 568-572.
38. Isogawa K, Haruo Nagayama H, Tsutsumi T, et al. Simultaneous use of thyrotropin-releasing hormone test and combined dexamethasone/corticotropine-releasing hormone test for severity evaluation and outcome prediction in patients with major depressive disorder. Journal of Psychiatric Research 2005;39:467–473.
39. Sullivan GM, Hatterer JA, Herbert J, Chen X, Rosse SP. Low levels of transthyretin in CSF of depressed patients. Am J Psych 1999;156:710-715.
40. Hatterer JA, Herbert J, Jidaka C, Roose SP, Gorman JM. CSF transthyretin in patients with depression Am J Psychiatry 1993;150:813-815.
41. Whybrow PC, Coppen A, Prange AJ, Noguera R, Bailey JE. Thyroid function and the response to liothyronine in depression. Arch Gen Psychiatry 1972;26:242-245.
42. Kirkegaard C, Faber J. Free thyroxine and 3,3’,5’-triiodothyroidnine levels in cerebralspinal fluid in patetns with endogenous depression. Acta Endorcinoligca 1991;124:166-172.
43. Kirkegaard C. The thyrotropin response to thyrotropin-releasing hormone in endogenous depression. Psychoneuroendocrinology 1981;6:189-212.
44. Baumgartner A, Graf KJ, Kurten I, Meinhold H. The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects Psychiatry Research 12988;24:271-332.
45. 150. D238. Stipcevic T, Pivac N, Kozarie-Kovacic D, Muck-Seler D. Thyroid activity in patients with major depression. Coll Antropol 2008;32(3):973-976.
46. Cheron RG, Kaplan MM, Larsen PR. Physiological and pharmacological influences on thyroxine to 3,5,3’-triiodothyronine conversion and nuclear 3,5,3’-triiodthyroidne binding in rat anterior pituitary. J Clin Invest 1979;64:1402-1414.
47. Araujo RL, Andrade BM, da Silva ML, et al. Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats. Am J Physiol Endocinol Metab 2009;296:E1157-E1163.
48. Leibel RL, Jirsch J. Diminished energy requirements in reduced-obese patients. Metabolism 1984;33(2):164-170.
49. Fontana L, Klein S, Holloszy JO, Premachandra BN. Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. J Clin Endocrinol Metab 2006;91(8):3232-3235.
50. Croxson MS, Ibbertson HK. Low serum triiodothyronine (T3) and hypothyroidism. J clin Endocrinol Metab 1977;44:167-174.
51. Silva JE, Larsen PR 1986 Hormonal regulation of iodothyronine 5-deiodinase in rat brown adipose tissue. Am J Physiol 251:E639-E643.
52. Krotkiewski M, Holm G, Shono N. Small doses of triiodothyronine can change some risk factors associated with abdominal obesity. Inter J Obesity 1997;21:922-929.
53. Krotkiewski M. Thyroid hormones and treatment of obesity. Int J of Obesity 2000;24(2):S116-S119.
54. Dagogo_Jack S. Human Leptin Regualtion and Promis in Pharmacotheroapy. Cur¬rent Drug Targets 2001;2:181-195.
55. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, et al. Serum immunoreactive-leptin. concentrations in normal-weight and obese humans New England Journal Medicine 1996;334: 292-295.
56. Dagogo-Jack S, Tanellis C, Paramore D, Brother SJ, Land TM. Plasma Leptin and Insulin Relationships in Obese and Nonobese Human, Diabetes 1996;45:695-698.
57. Maffei M et al. Leptin levels in human and rodent: measurement of plasma leptin and ob NAN in obese and weight-reduced subjects. Nature Medicine 1995;1;1155-1161.
58. Sandra G et al. Serum leptin in children with obesity. Relationship to gender and development 1996;98:201-203.
59. Kozlowska L, Rosolowska-Huszcz. Leptin, Thyrotropin, and Thyroid Hormones in Obese/Overweight Women Before and After Two Levels of Energy Deficit. Endocrine 2004;24(2):147-153.
60. Fekete C et al. Differential Effects of Central Leptin, Insulin, or Glucose Administra¬tion during Fasting on the Hypothalamic-Pituitary-Thyroid Axis and Feeding-Related Neurons in the Arcuate Nucleus. Endocrinology 2006;147(1):520-529.
61. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252.
62. Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. Leptin prevents fasting-in¬duced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997;138:2569–2576.
63. Zimmermann-Belsing T et al. Ciruclation leptin and thryoid dysfunction. Euro¬pean Journal of Endocrinology 2003;149:257-271.
64. Schwartz Mw, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000;404;61-671.
65. Mantzoros CS, Moschos SJ. Leptin: in search of role(s) in human physiology and path physiology. Clinical Endocrinology 1998;49:551-567.
66. Fruhbeck G, Jebb SA, Prentice AM. Leptin: physiology and pathophysiology. Clini¬cal Endocrinology 1998;49:551-567.
67. Flier JS, Harris M, Hollenber A. Leptin, nutrition and the thyroid: the why, the wherefore and the wiring. The Journal of clinical Investigation 2000;105(7):859-861.
68. Gon DW, He y, Karas M, Reitman M. Uncoupling protein-3 is a mediator of ther¬mogenesis regulated by thyroid hormone, beta 3-adernergic agonists and leptin. Jour¬nal of Biological Chemistry 1997;272:24129-24132.
69. Cusin I, Rouru J, Visser T, Burger AG, Rohner-Jeanrenaud F. Involvement of thy¬roid hormones in the effect of intracerebroventricular leptin infusion on uncoupling protein-3 expression in rat muscle. Diabetes 2000;49:1101–1105.
70. Rosenbaum M, Godmsith R et al. Low-dose leptin reverses skeletal muscle, au¬tonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest 2005;115:3579-3586.
71. Rosenbaum M, Muryphy et al. Low dose leptin administration reverses effects of sus¬tained weight-reduction on energy expenditure and circulation concentration of thyroid hormones. JCEM 2002:87(5):2391-2394.
72. Leibel RL et al. 1995. Changes in energy expenditure resulting from altered body weight. N Eng J Med. 332:621-28.
73. Rosenbaum M et al. The effects of changes in body and thyroid function. Amer J Clinical Nutrition 2000;71:1421-32.
74. Ahima, R et al. Role of leptin in the neuroendocrine response to fasting. Nat. 1996;382:250-52.
75. 249. L22. RosenbaumM. et al 1997 Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin. Endocrinol. Metab 1997;82:3647-54.
76. Legradi G et al. 1998. Leptin prevents fasting-induced suppression of prothyro¬tropin-releasing hormone messenger ribonucleic acid m neurons of the hypothalamic paraventricular nucleus. EndocrinoL 1998;138:2569-76.
77. Boozer C et al Synergy of leptin and sibutramine in treatment of diet-induced obe¬sity in rats. Metab. 2001;50:889-93.
78. Campfield LA et al. Recombinant mouse OB protein: Evidence for a peripheral sig¬nal linking adiposity and central neural networks. Sci 1995;269:546-48.
79. Farooqi I et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Eng J Med 1999;341:879-84.
80. Chehab F. Leptin as a regulator of adipose tissue mass and reproduction. Trends Pharmacol Sci 200;21:309-14.
81. Rosenbaum K et al. The role of leptin in human physiology. N Eng J Med 1999;341:913-15.
82. Naslund E et al. 2000. Associations of leptin, insulin resistance and thyroid func¬tion with long-term weight loss in dieting reduced-obese men. J Int Med, 248:299-308.
83. Doucette E, et at. 2000. Appetite after weight-loss by energy restriction and a low-fat diet-exercise follow up. Int J Obesity 2000;24:906-14.
84. Patricia Cristina Lisboa, Karen Jesus Oliveira, Adriana Cabanelas, Tania Maria Ortiga-Carvalho, and Carmen Cabanelas Pazos-Moura Acute cold exposure, leptin, and somatostatin analog (octreotide) modulate thyroid 5′-deiodinase activity
Am J Physiol Endocrinol Metab 2003;284:E1172-E1176.
85. Cabanelas, A (A); Lisboa, P C (PC); Moura, E G (EG); Pazos-Moura, Leptin acute modulation of the 5′-deiodinase activities in hypothalamus, pituitary and brown adipose tissue of fed rats. Hormone and metabolic research 2006;38 (8):481-5.
86. Cettour-Rose P, Burger AG, Meier CA, Visser TJ, et al. Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase. Am J Physiology Endocrinol Metab 2002;283(5):E980-7.
87. Fekete C, Kelly J, Mihaly E, Sarkar S, Rand WM, Legradi G et al. Neuropeptide Y has a central inhibitory action on the hypothalamic–pituitary–thyroid axis. Endocrinology 2001;142:2606–2613.
88. Fekete C, Legradi G, Mihaly E, Huang QH, Tatro JB, Rand WM, et al. a-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. Journal of Neuroscience 2000;20:1550–1558.
89. Legradi G, Emerson CH, Ahima RS,et al. Arcuate nucleus ablation prevents fasting-induced suppression of ProTRH mRNA in the hypothalamic paraventricular nucleus. Neuroendocrinology 1998;68:89–97.
90. Vignati L, Finley RJ, Hagg S, Aoki TT. Protein conservation during prolonged fast: a function of triiodothyronine levels. Trans Assoc Am Physicians 1978;91:169-179.
91. Katzeff HL, Selgrad C. Impaired peripheral thyroid hormone metabolism in genetic obesity. Endocrinology 1993;132(3):989-995.
92. Islam S, Yesmine S, Khan SA, Alam NH, Islam S. A comparative study of thyroid hormone levels in diabetic and non-diabetic patients. SE Asian J Trop Med Public Health 2008;39(5):913-916.
93. Pittman CS, Suda AK, Chambers JB, McDaniel HG, Ray GY. Abnormalities of thyroid hormone turnover in patients with diabetes mellitus before and after insulin therapy. JCEM 1979;48(5):854-60.
94. Saunders J, Hall SHE, Sonksen PH. Thyroid hormones in insulin requiring diabetes before and after treatment. Diabetologia 1978;15:29-32.
95. Chamras H, Hershman JM. Effect of diabetes mellitus on thyrotropin release from isolated rat thyrotrophs. Am J Med Sci 1990;300(1):16-21.
96. Ortiga-Carvalho TM, Curty FH, Nascimento-Saba CC, Moura EG, et al. Pituitary neuromedin B content in experimental fasting and diabetes mellitus and correlation with thyrotropin secretion. Metabolism 1997;46(2):149-153.
97. Jolin T, Gonzalez C. Thyroid iodine metabolism in streptozotocin-diabetic rats. Acta Endocrinologica 1978;88:506-516.
98. Montoya E, Gonzalez C, Lamas L, Jolin T. Changes of the hypothalamus-pituitary-thyroid axis in streptozotocin-diabetic rats during adaptation to a low iodine diet. Acta Endocrinologica 1978;88:721-728.
99. Pericas I, Jolin T. The effect of streptozotocin-induced diabetes on the pituitary-thyroid axis in goitrogen-treated rats. Acta Endocriniologica 1977;86:128-139.
100. Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499–518.
101. Fliers E, Alkemade A, Wiersinga WM. The hypothalamic-pituitary-thyroid axis in critical illness. Best Practice & Research Clinical Endocrinology & Metabolism 2001;15(4):453–64.
102. Chopra IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34.
103. Nagaya T, Fujieda M, Otsuka G, et al. A potential role of activated NF-Kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106(3):393–402.
104. Chopra IJ, Solomon DH, Hepner GW, et al. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979;90(6):905–12.
105. Van der Poll T, Romijn JA, Wiersinga WM, et al. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71(6):1567–72.
106. Stouthard JM, van der Poll T, Endert E, et al. Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 1994;79(5):1342–6.
107. Corssmit EP, Heyligenberg R, Endert E, et al. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. Clin Endocrinol Metab 1995;80(11):3140–4.
108. Nagaya T, Fujieda M, Otsuka G, et al. A potential role of activated NF-Kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106(3):393–402.
109. Zoccali C, Tripepi G, Cutrupi S, et al. Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J Am Soc Nephrol 2005;16:2789–95.
110. Chopra IJ, Sakane S, Teco GNC. A study of the serum concentration of tumor necrosis factor-_ in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab 1991;72:1113–1116.
111. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3_-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1695-1699
112. Hashimoto H, Igarashi N, Yachie A, Miyawaki T, et al. The relationship between serum levels of interleukin-6 and thyroid hormone in children with acute respiratory infection. J Clin Endocrinol Metab 1994;78: 288-291.
113. van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endo Metab 1990;71:1567-1572.
114. Altomonte L et al. Serum levels of interleukin-1alpha, tumor necrosis factor-alpha and interleukin-2 in rheumatoid arthritis. Correlation with disease activity. Clin. Rheumatol 1992;11(2)202–205
115. Espersen, G. T. et al. Tumor necrosis factor-alpha and interleukin-2 in plasma from rheumatoid arthritis patients in relation to disease. Clin Rheumatol 1991;10(4)374-376.
116. Morley JE. The endocrinology of the opiates and opioid peptides. Metabolism 1981;30(2):195-209.
117. Krulich L, Giachetti A, Marchlewska-Koj A, et al. On the role of central norandrenergic and dopaminergic systems in the regulation of TSH secretion in the rat. Endocrinology 1977;100:496-505.
118. Lomax P, Kokka N, George R. Thyroid activity following intracerbral injection of morphine in the rat. Neuroendocrinolgoy 1970;6(146):152.
119. Morley JE, Yamada T, Shulkes A, et al. Effects of morphine addiction and withdrawal on thyrotropin releasing hormone (TRH), somatostatin (SLI) and vasoactive intestinal peptide (VIP). Clin Res 1979;27:75A.
120. Dons RF. Changes in Triiodothyronine mark severe pain syndrome: A case report. Military medicine 1994;159:6:465.
121. Lowe JC, Garrison RL, Reichman AJ, et al. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled response-driven crossover study. Clinical Bulletin of Myofascial Therapy 1997;2(2/3):31-58.
122. Lowe JC, Reichman AJ, Yellin J. The process of change during T3 treatment for euthyroid fibromyalgia: a double-blind placebo-controlled crossover study. Clinical Bulletin of Myofascial Therapy 1997;2(2/3):91-124.
123. Lowe JC, Garrison RL, Reichman AJ, et al. Triiodothyronine (T3) treatment of euthyroid fibromyalgia: a small-n replication of a double-blind placebo-controlled crossover study. Clinical Bulletin of Myofascial Therapy 1997;2(4):71-88.
124. Yellin BA, Reichman AJ, Lowe JC. The process of Change During T3 Treatment for Euthyroid Fibromyalgia: A Double-Blind Placebo-Controlled Crossover Study. The Metabolic Treatment of Fibromyalgia. McDowell Publishing 2000.
125. Neeck G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheumatol 1992;19(7):1120-1122.
126. Watanabe C, Yoshida K, Kasanuma Y, Kun Y, Satoh H.. In utero methylmercury exposure differentially affects the activities of selenoenzymes in the fetal mouse brain. Environ Res 1999;;80(3):208-14.
127. Ellingsen DG, Efskind J, Haug E, Thomassen Y, Martinsen I, Gaarder PI. Effects of low mercury vapour exposure on the thyroid function in chloralkali workers. J Appl Toxicol.2000;20(6):483-9.
128. Moriyama K, Tagami T, Akamizu T, Usui T, et al. Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrin Metab 2002;87(11):5185-5190.
129. Zoeller RT, Bansal R, Parris C. Bisphenol-A, an Environmental Contaminant that Acts as a Thyroid Hormone Receptor Antagonist in Vitro, Increases Serum Thyroxine, and Alters RC3/Neurogranin Expression in the Developing Rat Brain. Endocrinolgy 2005;146(2):607-12.
130. Santini F, Mantovani A, Cristaudo A, et al. Thyroid function and exposure to styrene. Thyriod 2008;18(10):1065-1069.
131. Meeker JD, Calafat AM, Hauser R. Di(2-ethylhexyl) Phthalate Metabolites May Alter Thyroid Hormone Levels in Men. Environ Health Perspect 2007;115:1029–1034.
132. Massart F, Massai G, Placidi G, Saggese G. Child thyroid disruption by environmental chemicals. Minerva Pediatrica 2004;58(1):47-53.
133. Heimeier, RB, Buchholz DR, Shi. YB. The xenoestrogen bisphenol A inhibits postembryonic vertebrate development by antagonizing gene regulation by thyroid hormone. Endocrinology 2009;150(6):2964-2973.
134. Lema, SC, JT Dickey, IR Schultz and P Swanson. Dietary exposure to 2,2´,4,4´-tetrabromodiphenyl ether (PBDE 47) alters thyroid status and thyroid hormone-regulated gene transcription in the pituitary and brain. Environmental Health Perspectives 2008;116:1694–1699.
135. De Groot Leslie J. Non-Thyrodial illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006;22:57-86.
136. Schilling JU, Zimmermann T, Albrecht S, et al. Low T3 syndrome in multiple trauma patients – a phenomenon or important pathogenetic factor? Medizinische Klinik 1999;3:66– 9.
137. Schulte C, Reinhardt W, Beelen D, et al. Low T3-syndrome and nutritional status as prognostic factors in patients undergoing bone marrow transplantation. Bone Marrow Transplant 1998;22:1171– 8.
138. Girvent M, Maestro S, Hernandez R, et al. Euthyroid sick syndrome, associated endocrine abnormalities, and outcome in elderly patients undergoing emergency operation. Surgery 1998;123:560–7.
139. Maldonado LS, Murata GH, Hershman JM, et al. Do thyroid function tests independently predict survival in the critically ill? Thyroid 1992;2:119–23.
140. Vaughan GM, Mason AD, McManus WF, et al. Alterations of mental status and thyroid hormones after thermal injury. J Clin Endocrinol Metab 1985;60:1221–5.
141. De Marinis L, Mancini A, Masala R, et al. Evaluation of pituitary-thyroid axis response to acute myocardial infarction. J Endocrinol Invest 1985;8:507 – 11
142. Kantor MJ, Leef KH, Bartoshesky L, et al. Admission thyroid evaluation in very-low-birthweight infants: association with death and severe intraventricular hemorrhage. Thyroid 2003;13:965–9.
143. Miyashita K, Murakami M, Iriuchijima T, Takeuchi T, Mori M. Regulation of rat liver type 1 iodothyronine deiodinasemRNA levels by testosterone. Mol Cell Endocrinol 1995;115:161–167
144. Harris AR, Vagenakis AG, Braverman LE. Sex-related differences in outer ring monodeiodination of thyroxine and 3,3_,5_- triiodothyronine by rat liver homogenates. Endocrinology 1979;104: 645–652.
145. Visser TJ, Leonard JL, Kaplan MM, Larsen PR. Kinetic evidence suggesting two mechanisms for iodothyronine 5_-deiodination in rat cerebral cortex. Proc Natl Acad Sci USA 1982;79:5080–5084.
146. Leonard JL. Dibutyryl cAMP induction of Type II 5’ deiodinase activity in rat brain astrocytes in culture. Biochem Biophys Res Commun 1988;151:1164–1172.
147. Silva JE, Gordon MB, Crantz FR, Leonard JL, Larsen PR. Qualitative and Quantitative differences in pathways of extrathyroidial triiodothyronine generation between euthyroid and hypothyroid rats. J. Clin Invest 1984;73:898-907.
148. Larsen PR. Thyroid-pituitary interaction: Feedback regulation of thyrotropin secretion by thyroid hormones. NEJM 1982; 306(1):23-32.
149. Silva JE, Larsen PR. Pituitary nuclear 3,5,3′-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science, 1977;198(4317):617-620.
150. Schimmel M, Utiger RD. Thyroidal and peripheral production of thyroid hormones: review of recent finding and their clinical implications. Ann Intern Med 1977;87:760-8.
151. Silva JE, Leonard JL, Crantz FR, Larsen PR. Evidence for two tissue specific pathways for in vivo thyroxine 5_deiodination in the rat. J Clin Invest 1982;69:1176–1184.
152. Silva JE, Larsen PR 1978 Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine to nuclear triiodothyronine receptor saturation in pituitary, liver, and kidney of hypothyroid rats: further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release. J Clin Invest 61:1247– 1259
153. Silva JE, Dick TE, Larsen PR. The contribution of local tissue thyroxine monodeiodination to the nuclear 3,5,3_-triiodothyronine in pituitary, liver, and kidney of euthyroid rats. Endocrinology 1978;103:1196–1207.
154. Bianco AC, Silva JE. Nuclear 3,5,3_-triiodothyronine (T3) in brown adipose tissue: receptor occupancy and sources of T3 as determined by in vivo techniques. Endocrinology 1987;120:55–62
155. van Doorn JD, Roelfsema F, van der Heide D. Contribution from local conversion of thyroxine to 3,5,3_-triiodothyronine to cellular 3,5,3_-triiodothyronine in several organs in hypothyroid rats at isotope equilibrium. Acta Endocrinol (Copenh) 1982;101:386–406.
156. van Doorn JD, van der Heide D, Roelfsema F 1983 Sources and quantity of 3,5,3_-triiodothyronine in several tissues of the rat. J Clin Invest 72:1778–1892.
157. van Doorn JD, Roelfsema F, van der HeideD. Concentrations of thyroxine and 3,5,3_-triiodothyronine at 34 different sites in euthyroid rats as determined by an isotopic equilibrium technique. Endocrinology 1985;117:1201–1208.
158. Eales JG, McLeese JM, Holmes JA, Youson JH. Changes in intestinal and hepatic thyroid hormone deiodination during spontaneous metamorphosis of the sea lamprey, Petromyzon marinus. J Exp Zool 2000;286:305–312.
159. Croteau W, Davey JC, Galton VA, St. Germain DL. Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. J Clin Invest 1996;98:405–417.
160. Gereben B, Bartha T, Tu HM, Harney JW, Rudas P, Larsen PR. Cloning and expression of the chicken type 2 iodothyronine 5_-deiodinase. J Biol Chem 1999;274:13768–13776.
161. Tu HM, Kim SW, Salvatore D, Bartha T, et al. Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 1997;138:3359–3368.
162. Leonard JL, Kaplan MM, Visser TJ, Silva JE, Larsen PR. Cerebral cortex responds rapidly to thyroid hormones. Science 1981;214:571–573.
163. Burmeister LA, Pachucki J, St. Germain DL. Thyroid hormones inhibit type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre- and posttranslational mechanisms. Endocrinology 1997;138:5231–5237.
164. Salvatore D, Bartha T, Harney JW, Larsen PR. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 1996;137:3308–3315.
165. Hosoi Y, Murakami M, Mizuma H, Ogiwara T, et al. Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells. J Clin Endocrinol Metab 1999;84:3293–3300.
166. Riskind PN, Kolodny JM, Larsen PR. The regional hypothalamic distribution of type II 5_-monodeiodinase in euthyroid and hypothyroid rats. Brain Res 1987;420:194–198
167. Guadano-Ferraz A, Obregon MJ, St. Germain DL, Bernal J. The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci USA 1997;94:10391–10396.
168. Berry MJ, Banu L, Larsen PR. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 1991;349:438–440.
169. Maia AL, Berry MJ, Sabbag R, Harney JW, Larsen PR. Structural and functional differences in the dio1 gene in mice with inherited type 1 deiodinase deficiency. Mol Endocrinol 1995;9:969–980.
170. Kaplan MM, Utiger RD 1978 Iodothyronine metabolism in liver and kidney homogenates from hypothyroid and hyperthyroid rats. Endocrinology 1978;103:156–161.
171. Harris ARC, Fang SL, Vagenakis AG, Braverman LE. Effect of starvation, nutrient replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat. Metabolism 1978;27:1680–1690.
172. Berry MJ, Kates AL, Larsen PR. Thyroid hormone regulates type I deiodinase messenger RNA in rat liver. Mol Endocrinol 1990;4:743–748.
173. Maia AL, Harney JW, Larsen PR. Pituitary cells respond to thyroid hormone by discrete, gene-specific pathways. Endocrinology 1995;136:1488–1494.
174. van der Poll T, Romijn JA, Wiersinga WM, et al. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71(6):1567–72.
175. Stouthard JM, van der Poll T, Endert E, et al. Effects of acute and chronic interleukin- 6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 1994;79(5):1342–6.
176. Corssmit EP, Heyligenberg R, Endert E, et al. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. Clin Endocrinol Metab 1995;80(11):3140–4.
177. Annewieke W, van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab 2005;90(12):6403–9.
178. Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3′,5′- triiodothyronine (reverse T3) and 3,3′5-triiodothyronine (T3). JCEM 1975;41:911-920.
179. Danforth EJ, Desilets EJ, Jorton ES, Sims EAH, et al. Reiprocal serum triiodothryronine (T3) and reverse (rT3) induced by altering the carbohydrate content of the diet. Clin Res 1975;23:573.
180. Palmbald J, Levi J, Burger AG, Melade H, Westgren U, et al. Effects of total energy withdrawal (fasting) on the levels of growth hormone, thryrotropin, cortisol, noradrenaline, T4, T3 and rT3 in healthy males. Acta Med Scand 1977;201:150.
181. De Jong F, den Heijer T, Visser TJ, et al. Thyroid hormones, dementia, and atrophy of the medical temporal lobe. J Clin Endocrinol Met 2006;91(7):2569–73. high reverese t3 with brain atrophy.
182. Goichot B, Schlienger JL, Grunenberger F, et al. Thyroid hormone status and nutrient intake in the free-living elderly. Interest of reverse triiodothyronine assessment. Eur J Endocrinol 1994;130:244–52.
183. Visser TJ, Lamberts WJ, Wilson JHP, Docter WR, Hennemann G. Serum thyroid hormone concentrations during prolonged reduction of dietary intake. Metabolism 1978;1978;27(4):405-409.
184. Okamoto R et al. Adverse effects of reverse triiodothyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy. Res Exp Med (Berl) 1997;197(4):211-7. blocks T3 lower metabolism
185. Tien ES, Matsui K, Moore R, Negishi M. The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J Pharmacol Exp Ther. 2007;320(1):307-13.
186. Benvenga S, Cahnmann HJ, and Robbins J. Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain. Endocrinology 1993;133:1300–1305.
187. Sechman A, Niezgoda J, Sobocinski R. The relationship between basal metabolic rate (BMR) and concentrations of plasma thyroid hormones in fasting cockerels. Follu Biol 1989;37(1-2):83-90.
188. Pittman JA, Tingley JO, Nickerson JF, Hill SR. Antimetabolic activity of 3,3’,5’-triiodo-dl-thyronine in man 1960; Metabolism;9:293-5.
189. Santini F, Chopra IJ, Hurd RE, Solomon DH, Teco GN 1992 A study of the characteristics of the rat placental iodothyronine 5-monodeiodinase: evidence that is distinct from the rat hepatic iodothyronine 5-monodeiodinase. Endocrinology 130:2325–2332.
190. Silva JE, Leonard JL. Regulation of rat cerebrocortical and adenophypophyseal type II 5’-deidodinase by thyroxinem triiodothyronine, and reverse triiodothyronine. Endocrinology 1985;116(4):1627-1635.
191. Obregon MJ, Larsen PR, Silva JE. The Role of 3,3’,5’-triiodothyroinine in the regulation of type II iodothyronin 5’-deiodinase in the rat cerebral cortex. Endocrinology 1986;119(5):2186-2192.
192. Chopra IJ. A study of extrathyroidal conversion of thyroxine (T4) to 3,3′,5-triiodothyronine (T3) in vitro. Endocrinology. 1977;101(2):453-63
193. Mitchell AM, Manley SW, Rowan KA, Mortimer RH. Uptake of reverse T3 in the human choriocarcinoma cell line Jar. Placebta 1999;20:65-70.
194. Van der Geyten S, Buys N, Sanders JP, Decuypere E, et al. Acute pretranslational regulation of type III iodothyronine deiodinase by growth hormone and dexamethasone in chicken embryos. Mol Cell Endocrinol 1999;147:49–56.
195. Peeters RP, Wouters PJ, van Toor H, et al. Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90(8):4559–65.
196. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:3202–11.
197. Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63(1):1-8.
198. 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… J Clin Invest 1995;96(6):2828–2838.
199. Lomenick JP, El-Sayyid M, Smith WJ . Effect of levo-thyroxine treatment on weight and body mass index in children with acquired hypothyroidism. The Journal of Pediatrics 2008;152(1):96-100.
200. Acker CG, Singh AR, Flick RP, et al. A trial of thyroxine in acute renal failure. Kidney Int 2000;57:293-8.
201. Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid 2007;17(3):249-58.
202. Cooke RG, Joffe RT, Levitt AJ. T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. J Clin Psychiatry1992;53(1):16-8.
203. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Tri-idothyronine treatment in children after cardiac surgery: a double-blind, randomized, placebo-controlled study. The Lancet 2000;356:529-534.
204. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothryronine replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized placebo-controlled study. J Clin Endocrin Metab 2008;93(4):1351-8.
205. Meyer T, Husch M, van den Berg E, et al. Treatment of dopamine-dependent shock with triiodothyronine: preliminary results. Deutsch Med Wochenschr 1979;104:1711-14.
206. Dulchavsky SA, Hendrick SR, Dutta S. Pulmonary biophysical effects of triiodothyronine (T3) augmentation during sepsis induced hypothyroidism. J Trauma 1993;35:104-9.
207. Novitzsky D, Cooper DKC, Human PA, et al. Triiodothyronine therapy for heart donor and recepient. J Heart Transplant 1988;7:370-6.
208. Dulchavsky SA, Maitra SR, Maurer J, et al. Beneficial effects of thyroid hormone administration in metabolic and hemodynamic function in hemorrhagic shock. FASEB J 1990;4:A952.
209. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:1522-7.
210. Gomberg-Maitland M. Thyroid hormone and cardiovascular disease. Am Heart J 1998;135:187-96.
211. Dulchavsky SA, Kennedy PR, Geller ER, et al. T3 preserves respiratory function in sepsis. J Trauma 1991;31:753–9.
212. Novitzky D, Cooper DK, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987;43:852–5.
213. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81:443–7.
214. Klemperer JD, Klein IL, Ojamaa K, et al. Triidothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323–9.
215. Smidt-Ott UM, Ascheim DD. Thyroid hormone and heart failure. Curr Heart Fail Rep 2006;3:114–9.
216. LoPresti JS, Eigen A, Kaptein E, Anderson KP, et al. Alterations in 3,3’5’-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man. J Clin Invest 1989;84:1650–1656.
217. Cremaschi GA, Gorelik G, Klecha AJ, Lysionek AE, Genaro AM. Chronic stress influences the immune system through the thyroid axis. Life Sci. 2000 Nov 17;67(26):3171-9.
218. Burr WA, Ramsden DB, Griffiths RS, Black EG, Hoffenberg R, et al. Effect of a single dose of dexamethasone on serum concentrations of thyroid hormones. Lancet. 1976;10;2(7976):58-61.
219. Saranteas T, Tachmintzis A, Katsikeris N, Lykoudis E, Mourouzis I,et al. Perioperative Thyroid Hormone Kinetics in Patients Undergoing Major Oral and Maxillofacial Operations J Oral Maxillofac Surg 2007;65:408-414.
220. Joffe RT. A perspective on the thyroid and depression. Can J Psychiatry 1990;35(9):754-8.
221. Posternak M, Novak S, Stern R, Hennessey J, Joffe R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacology 2008;11:15–25.
222. Wekking EM, Appelhof BC, Fliers E, Schene AH, et al. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. European J Endocrinol 2005;153:747-753.
223. Escobar-Morreale HF, Escobar del Rey F, Obregon MJ, Morreale de Escobar G. Only the combined treatment with thyroxine and triiodothryoidine ensures euthyroidism in all tissue… Endocrinology 1996;137:2490-2502.
224. Duick DS, Warren DW, Nicoloff JT, Otis CL, Croxson MS. Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab. 1974 ;39(6):1151-4.
225. Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improved depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88(10):4551-4555.
226. Cooper-Kazaz R, Apter JT, Cohen R, Karagichev L, et al. Combined treatment with sertraline and liothyronine in major depression. Arch Gen Psych 2007;64:679-688.
227. Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment resistant bipolar II and bipolar disorder NOS. Journal of Affective Disord 2009;116:222-226.
228. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry 2006;163:1519-1530.
229. Tennant F. Hormone Treatments in chronic and intractable pain. Practical Pain Management 2005; 57-63.
230. Dore C, Hesp R. Wilkins D, et al. Prediction of energy requirements of obese patients after massive weight loss. Human Nutr clin Nutr 1982;366:41-48.
231. Apfelbaum M, Bostsarron J, Lacatis D. Effects of caloric restriction and excessive caloric intake on energy expenditure. Am J Clin Nutr 1971;24:1405-1410.
232. Drenick EJ, Dennin HF. Energy expenditure in fasting obese men. J Lab Clin Med 1973;81:421-430.
233. Silva JE, Larsen PR. Interrelationships among thyroxine, growth hormone, and the sympathetic nervous system in the regulation of 5-iodothyronine deiodinase in rat brown adipose tissue. J Clin Invest 1986;77:1214-1223.
234. Lim VS, Passo C, Murata Y, Ferrari E, et al. Reduced triiiodthyronine content in liver but not pituitary of the uremic rat model: demonstration of changes compatible with thyroid hormone deficiency in liver only. Endocrinology 1984;114(1):280-286.
235. Tulp OL, Mckee TD. Thiiodothyronine (T3) neogenesis in lean and obese LA/N-cp rats. Biochem Biophys Research Comm 1986;140(1)134-142.
236. Loucks AB, Heath EM. Induction of low-T3 syndrome in exercising women occurs at the threshold of energy availability. Am J Physiol Regul Integr Comp Physiol 1994;266: R817-R823.
237. Opstad PK, Falch D, Oktedalen O, Fonnum F, Wergeland R. The thyroid function in young men during prolonged exercise and the effect of energy and sleep deprivation. Clinical Endocrinology 1984;20:657-669.
238. Dillman E, Gale C, Green W, et al. Hypothermia in iron deficiency due to altered triiodithyroidine metabolism. Regulatory, Integrative and Comparative Physiology 1980;239(5):377-R381.
239. Smith SM, Johnson PE, Lukaski HC. In vitro hepatic thyroid hormone deiodination in iron-deficient rats: effect of dietary fat. Life Sci 1993;53(8):603-9.
240. Eftekhari MH, Keshavarz SA, Jalali M. The relationship between iron status and thyroid hormone concentration in iron-deficient adolescent Iranian girls. Asia Pac J Clin Nutr 2006;15 (1):50-55.
241. Zimmermann MB, Köhrle J. The Impact of Iron and Selenium Deficiencies on Iodine and Thyroid Metabolism: Biochemistry and Relevance to Public Health. Thyroid 2002;12(10): 867-78.
242. Beard J, tobin B, Green W. Evidence for Thyroid Hormone Deficiency in Iron-Deficient Anemic Rats. J. Nutr. 1989;119:772-778.
243. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS.Exposure to physical and psychological stressors elevates plasma interleukin-6: relationship to the activation of the hypothalamic–pituitary–adrenal axis. Endocrinology 1993;133:2523–30.
244. Brunner EJ, Marmot MG, Nanchahal K, et al. Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall II Study. Diabetologia 1997;40:1341–9.
245. Miller GE, Blackwell E. Turning Up the Heat: Inflammation as a Mechanism Linking Chronic Stress, Depression, and Heart Disease. Current Directions in Psychological Science 2009;15(6):269-272.
246. Ranjit N, Diez-Roux AV, Shea S, et al. Psychosocial factors and inflammation in the Multi-Ethnic Study of Atherosclerosis. Arch Intern Med 2007;167:174-181.
247. Davis MC, Zautra AJ, Younger J, Motivala SJ, et al. Chronic Stress and Regulation of Cellular Markers of Inflammation in Rheumatoid Arthritis: Implications for Fatigue. Brain Behav Immun 2008 January; 22(1):24-32.
248. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 2(1):209-214.
249. Tilg H, Moschen AR. Insulin resistance, inflammation, and non-alcoholic fatty liver disease., Trends in endocrinology and metabolism 2008;19(10):371-9.
250. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Human subcutaneous adipose tissue secretes interleukin-6 but not TNF-a in vivo. J Clin Endocrinol Metab 1997;82:4196-200.
251. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor- a in human obesity and insulin resistance. J Clin Invest 1995;95:2409-15.
252. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847–50.
253. Liu S, Tinker L, Song Y, Rifai N, et al. A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. Arch Intern Med 2007;167(15):1676-85.
254. Leonard BE. Inflammation, depression and dementia: are they connected? Neurochem Res 2007;32(10):1749-56.
255. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19(1):11-38.
256. Maes M, Scharpé S, Meltzer HY, Bosmans E, et al. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res 1993;49(1):11-27.
257. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19(1):11-38.
258. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflamatory cytokine activity after menopause. Endocrine Rev 2002;22(1):90-119.
259. Alexander RW. Inflammation and coronary artery disease. New Engl J Med 1994;331:468–9.
260. MRFIT Research Group, Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996;144:537–47.
261. Khan G. Epstein-Barr virus, cytokines, and inflammation: a cocktail for the pathogenesis of Hodgkin’s lymphoma? Exp Hematol 2006;34(4):399-406.
262. Takeshita S, et al. Induction of IL-6 and IL-10 production by recombinant HIV-1 envelope glycoprotein 41 (gp41) in the THP-1 human monocytic cell line. Cell Immunol 1995;165(2):234-242.
263. Reinecker HC,et al. Enhanced secretion of tumor necrosis factor, IL-6, and IL-1 by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn´s disease. Clin. Exp. Immunol 1993;94(1)174-181.
264. Gross V, et al. Inflammatory mediators in chronic inflammatory bowel disease. Klin Wochenschr 1991;69(21–23):981–987.
265. Benvenuto, R. et al. Tumor necrosis factor-alpha and interferon-alpha synthesis by cerebrospinal fluid-derived T cell clones in multiple sclerosis. Ann. N.Y. Acad Sci 1992;650, 341–346.
266. Cohen MC, Cohen S. Cytokine function: a study in biologic diversity. Am J Clin Pathol 1996;105:589–598.
267. Coussens LM, et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 1999;13:1382-1397.
268. Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer 2003;97:2919-2925.
269. Lee BN, Dantzer R, Langley KE, et al. A cy¬tokine-based neuroimmunologic mechanism of cancer related symptoms. Neuroimmunomodulation 2004;11:279-292.
270. Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. Thyroid function, endothelium, and inflammation in hemodialyzed patients: Possible relations? J Renal Nutrition 2007;17(1):30-37.
271. Boelen A, Kwakkel J, Alkemade A, Renckens R, et al. Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation. Endocrinology 2005;146(12):5128-5134.
272. Hesch RD, Brunner G, Soling HD. Conversion of thyroxine (T4) and triiodothyronine (T3) and the subcellular localization of the converting enzyme. Clin Chim Acta 1975;59:209–213.
273. Visser TJ, van der Does-Tobe I, Docter R, Hennemann G. Conversion of thyroxine into triiodothyronine by rat liver homogenate. Biochem J 1975;150:489–493.
274. Lakind JS, Naiman DQ. Biphenol A (BPA) daily intakes in the United States: Estimates form the 2003-2004 NHANES urninary BPA data. J Exposure Envirom Epidemiology 2008;18:608-615.
275. Cone M. Californians have world’s highest levels of flame retardants. Environmental Health News October 1, 2008.
276. Travison TG, Araujo AB, O’Donnell AB, et al. A Population-Level Decline in Serum Testosterone Levels in American Men J. Clin Endocrinol Metab 2006;92:196-202.
277. Kupelian V, Hayes FJ, Link CL, et al. Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. J Clin Endocrinol Metab 2008;93:3403–3410.
278. Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: Correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30(4):911-7.
279. Makhsida N, Shah J, Yan G. Hypogonadism and metabolic syndrome: Implications for testosterone therapy. J Urology 2005;174:827-834.
280. Jorgensen JOL, Pedersen SA, Laurberg P, Weeke J, et al. Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab 1989;69:1127-1132
281. Darras VM, Berghman LR, Vanderpooten A, Kuhn ER. Growth hormone acutely decreases type III deiodinase in chicken liver. FEBS Lett 1992;310:5-8.
282. Takser L, Mergler D, Baldwin M, de Grosbois S, et al. Thyroid hormones in pregnancy in relation to environmental exposure to organochlorine compounds and mercury. Environmental Health Perspectives 2005;113(8):1039-1045.
283. De Jong FJ, Peeters RP, Jeijer TD, van der Deure WM, Hofman A, et al. The association of pohymorphism in the type 1 and 2 deiodinase genes with circulation thyroid hormone parameters and atrophy of the medial Temporal lobe. JCEM 2007;92(2):636-640.