Hypothyroidism is a common disorder where there is inadequate cellular thyroid effect to meet the needs of the tissues. Typical symptoms of hypothyroidism include fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention, premenstrual syndrome (PMS) and dry skin. Low thyroid causes or contributes to the symptoms of many conditions but the deficiency is often missed by standard thyroid testing. This is frequently the case with depression, hypercholesterolemia (high cholesterol), menstrual irregularities, infertility, PMS, chronic fatigue syndrome (CFS), fibromyalgia, fibrocystic breasts, polycystic ovary syndrome (PCOS), hyperhomocysteinuria (high homocystine), atherosclerosis, hypertension, obesity, diabetes and insulin resistance.
The TSH is thought to be the most sensitive marker of peripheral tissue levels of thyroid, and it is erroneously assumed by most endocrinologists and other physicians that, except for unique situations, a normal TSH is a clear indication that the person’s tissue thyroid levels are adequate (symptoms are not due to low thyroid) (see why doesn’t my doctor know this). A more thorough understanding of the physiology of hypothalamic-pituitary-thyroid axis and tissue regulation of thyroid hormones demonstrates that the widely held belief that the TSH is an accurate marker of the body’s overall thyroid status is clearly erroneous.
The TSH is inversely correlated with pituitary T3 levels but with physiologic stress (1-32), depression (33-38), insulin resistance and diabetes (28,39,116,117), aging (30,40-49), calorie deprivation (dieting)(27, 50-57), inflammation (5-8,22,108,109-111), PMS (58,59), chronic fatigue syndrome and fibromyalgia (60,61), obesity (112,113,114) and numerous other conditions (1-32), increasing pituitary T3 levels are often associated with diminished cellular and tissue T3 levels and increased reverse T3 levels in the rest of the body (1-62) (see pituitary diagram). The pituitary is both anatomically and physiologically unique, reacting differently to inflammation and physiologic stress than every other tissue in the body (1-20,50-52,62,63)(see deiodinase). The conditions above stimulate local mechanisms to increase pituitary T3 levels (reducing TSH levels) while reducing T3 levels in the rest of the body (1-63). Thus, with physiologic or emotional stress, depression or inflammation, the pituitary T3 levels do not correlate with T3 levels in the rest of the body, and thus, the TSH is not a reliable or sensitive marker of an individual’s true thyroid status (see deiodinase).
Serum levels of thyroid hormones
(see serum thyroid hormones graph)
Due to the differences in the pituitary’s response to physiological stress, depression, dieting, aging and inflammation as discussed, most individuals with diminished tissue levels of thyroid will have a normal TSH (1-63). Doctors are taught that if active thyroid (T3) levels drop, the TSH will increase. Thus, endocrinologists and other doctors tell patients that an elevated TSH is the most useful marker for diminished T3 levels and that a normal TSH indicates that their thyroid status is “fine”. The TSH is, however, merely a marker of pituitary levels of T3 and not of T3 levels in any other part of the body. Only under ideal conditions of total health do pituitary T3 levels correlate with T3 levels in the rest of the body, making the TSH a poor indicator of the body’s overall thyroid status. The relationship between TSH and tissue T3 is lost in the presence of physiologic or emotional stress (1-32), depression (33-38), insulin resistance and diabetes (28,39), aging (30,40-49)(see thyroid hormones and aging graph), calorie deprivation (dieting)(50-57), inflammation (5-8,22), PMS (58,59), chronic fatigue syndrome and fibromyalgia (60,61), obesity (112,113,114) and numerous other conditions (1-63). In the presence of such conditions, the TSH is a poor marker of active thyroid levels and thyroid status of an individual, and a normal TSH cannot be used as a reliable indictor that a person is euthyroid (normal thyroid) in the overwhelming majority of patients.
Value of Serum T4
The suppression of TSH with physiologic and emotional stress and illness suppresses the production of T4 (1,2,9,64-68), which would tend to lower serum T4 levels. In the presence of such conditions, there are, however, competing effects that result in an increase in serum T4 while further reducing tissue levels of T3 levels, making serum T4 (or free T4) a poor marker of tissue thyroid level, as is the case with the TSH. Such effects include a suppression of tissue T4 to T3 conversion (misleadingly increasing serum T4 levels) (1-68,76) with an increased conversion of T4 to reverse T3 (12,14,18,35,36,41,59,69-74,85) and an induced thyroid resistance with reduced uptake of T4 into the cells (misleadingly increasing serum T4 levels) (16,1976-84) in all tissues except for the pituitary (84). Although all such effects reduced intracellular T3 in all tissues except for the pituitary, the serum T4 level can be increased, decreased or unchanged. Consequently, serum T4 levels oftentimes do not correlate with tissue T3 levels and, as with the TSH, the serum T4 level is often misleading and an unreliable marker of the body’s overall thyroid status (see serum thyroid levels in stress and illness).
Current best method to diagnosis
With increasing knowledge of the complexities of thyroid function at the cellular level, it is becoming increasingly clear that TSH and T4 levels are not the reliable markers of tissue thyroid levels as once thought, especially with chronic physiologic or emotional stress, illness, inflammation, depression and aging. It is common for an individual to complain of symptoms consistent with hypothyroidism but have normal TSH and T4 levels. While there are limitations to all testing and there is no perfect test, obtaining free triiodothyronine, reverse triiodothyronine, and triiodothyronine/reverse-triiodothyronine ratios can be helpful to obtain a more accurate evaluation of tissue thyroid status and may be useful to predict those who may respond favorably to thyroid supplementation (1,11,12,14,18,35,36,41,59,69-74,85) (see serum thyroid levels in stress and illness). Many symptomatic patients with low tissue levels of active thyroid hormone but normal TSH and T4 levels significantly benefit from thyroid replacement, often with significant improvement in fatigue, depression, diabetes, weight gain, PMS, fibromyalgia and numerous other chronic conditions (86-99).
With an understanding of thyroid physiology, it becomes clear why a large percentage of patients treated with T4 only preparations continue to be symptomatic. Thyroxine (T4) only preparations should not be considered the treatment of choice and are often not effective in conditions associated with reduced T4 to T3 conversion, reduced uptake of T4 or increased T4 to reverse T3 conversion. As discussed above, with any physiologic stress (emotional or physical), inflammation, depression, inflammation, aging or dieting, T4 to T3 conversion is reduced and T4 will be preferentially converted to reverse T3 (12,14,18,35,36,41,53,69-74,85), which acts a competitive inhibitor of T3 (blocks T3 at the receptor) (100-104), reduces metabolism (100,103,104), suppresses T4 to T3 conversion (101,103) and blocks T4 and T3 uptake into the cell (105).
While a normal TSH cannot be used as a reliable indicator of global tissue thyroid effect, even a minimally elevated TSH (above 2) demonstrates that there is diminished intra-pituitary T3 level and is a clear indication (except in unique situations such as a TSH secreting tumor) that the rest of the body is suffering from inadequate thyroid activity because the pituitary T3 level is always significantly higher than the rest of the body and the most rigorously screened individuals for absence of thyroid disease have a TSH below 2 to 2.5 (106). Thus, treatment should likely be initiated in any symptomatic person with a TSH greater than 2. Additionally, many individuals will secrete a less bioactive TSH so for the same TSH level, a large percentage of individuals will have reduced stimulation of thyroid activity, further limiting the accuracy of TSH as a measure of overall thyroid status. Reduced bioactivity of TSH is not detected by current TSH assays used in clinical practice.
Due to the lack of correlation of TSH and tissue thyroid levels, as discussed, a normal TSH should not be used as the sole reason to withhold treatment in a symptomatic patient. A symptomatic patient with an above average reverse T3 level and a below average free T3 (a general guideline being a free T3/reverse T3 ratio less than 2) should also be considered a candidate for thyroid supplementation (13,14,18,69-76,85-106). A relatively low sex hormone binding globulin (SHBG) and slow reflex time can also be useful markers for low tissue thyroid and levels and can aid in the diagnosis of tissue hypothyroidism (93,107,115).
A study published in the Journal of Clinical Endocrinology and Metabolism assessed the level of hypothyroidism in 332 female patients based on a clinical score of 14 common signs and symptoms of hypothyroidism and assessments of peripheral thyroid action (tissue thyroid effect). The study found that the clinical score and ankle reflex time correlated well with tissue thyroid effect but the TSH had no correlation with the tissue effect of thyroid hormones (118). The ankle reflex itself had a specificity of 93% (93% of those with slow relaxation phase of the reflexes had tissue hypothyroidism) and a sensitivity of 77% (77% of those with tissue hypothyroidism had a slow relaxation phase of the reflexes) making both the measurement of the reflex speed and clinical assessment a more accurate measurement of tissue thyroid effect than the TSH.
A combination of the serum levels of TSH, free T3, free T4, reverse T3, anti-TPO antibody, antithyroglobulin antibody and SHBG should be used in combination of with clinical assessment and measurement of reflex speed and basal metabolic rate to most accurately determine the overall thyroid status in a patient. Forgoing treatment based on a normal TSH without further assessment will result in the misdiagnosis of mismanagement of a large number of hypothyroid patients that may greatly benefit with treatment. Simply relying a TSH to determine the thyroid status of a patient demonstrates a lack of understanding of thyroid physiology and is not evidence based medicine (see Why my Endocrinologist Doesn’t Know All of This). In patients with elevated or high normal reverse T3 levels, T4 only preparations should not be considered adequate and T3 containing preparations, in particular timed released T3, should be considered the treatment of choice.
1. Peeters RP, Geyten SV, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;12:6498–507.
2. 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.
3. 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.
4. Chopra IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34.
5. 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.
6. 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.
7. 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.
8. 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.
9. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodieidinases. Endocr Rev 2002;23:38–89.
10. Chopra IJ, Huang TS, Beredo A, et al. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3,5,3’-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985;60:666–72.
11. 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.
12. 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.
13. Iervasi G, Pinitore A, Landi P, et al. Low-T3 syndrome a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107(5): 708–13.
14. 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.
15. Wartofsky L, Burman K. Alterations in thyroid function in patients with systemic illness; the ‘‘euthyroid sick syndrome’’. Endocr Rev 1982;3(2):164–217.
16. Hennemann G, Everts ME, de Jong, et al. The significance of plasma membrane transport in the bioavailability of thyroid hormone. Clin Endocrinol 1998;48:1–8.
17. Vos RA, de Jong M, Bernard HF, et al. Impaired thyroxine and 3,5,3’-triodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthryoidal illness. J Clin Endocrinology met 1995;80:2364–70.
18. 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. Usefulness of rT3 in NTI
19. De Jong M, Docter R, Van Der Hoek HJ, et al. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131:463–70.
20. Mooradian AD, Reed RL, Osterweil D, et al. Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab 1990;71(5):1239–42.
21. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007;262:690–701.
22. 234. 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.
23. Zoccali C, Mallamaci F, Tripepi G, et al. Low triiodothyronine and survival in endstage renal disease. Kidney Int 2006;70:523–8.
24. Pingitore A, Landi P, Taddei MC, et al. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118(2):132–6.
25. Kozdag G, Ural D, Vural A, et al. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy.
Eur J Heart Fail 2005;7(1):113–8.
26. Karadag F, Ozcan H, Karul AB, et al. Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med 2007;101:1439–46.
27. Kok P, Roelfsema F, Langendonk JG, et al. High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction.. J Clin Endocrinol Metab 2005;90:4659–63.
28. Parr JH. The effect of long-term metabolic control on free thyroid hormone levels in diabetics during insulin treatment. Ann Clin Biochem 1987;24(5):466–9.
29. Dimopoulou I, Ilias I, Mastorakos G, et al. Effects of severity of chronic obstructive pulmonary disease on thyroid function. Metabolism 2001;50(12):1397–401.
30. Mariotti S, Barbesino G, Caturegli P, et al. Complex alterations of thyroid function in healthy centenarians. J Clin Endocrinol Met 1993;77(5):1130–4.
31. Nomura S, Pittman CS, Chambers JB, et al. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest 1975;
32. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine replacement therapy in patients with chronic heart failure and low T3 syndrome: a randomized placebo-controlled study. J Clin Endocrinol Met 2008;93:1351–8.
33. 268. Premachandra BN, Kabir MA, Williams IK, Low T3 syndrome in psychiatric depression. J Endocrinol Invest 2006;29:568-572.
34. Jackson I. The thyroid axis and depression. Thyroid 1998;8(10):952-956.
35. 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.
36. Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L. Reverse T3 levels in affective disorders. Psychiatry Research 1983;10:1-9.
37. 272. Stipcevic T, Pivax N, Kozaric-Kovacic D, Muck-Seler D. Thyroid activity in patients with major depression. Coll Antropol 2008;32(3):973-6.
38. Gold MS, Pottash LC, Extein I. Hypothyroidism and depression. JAMA 1981;245(19):1919-1922.
39. 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. 50% reduction in free t3 in diabetics.
40. Carle A, Laurberg P, Pedersen IB, et al. Thyrotropin secretion decreases with age in patients with hypothyroidism. Clinical Thyroidology 2007;17:139–44.
41. 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.
42. Van Coevorden A, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989;69:
43. Rubenstein HA, Butler VPJ, Werner SC. Progressive decrease in serum triiodothyronine concentrations with human aging: radioimmunoassay following extraction of serum. J Clin Endocrinol Metab 1973;37:247–53.
44. Chakraborti S, Chakraborti T, Mandal M, et al. Hypothalamic–pituitary–thyroid axis status of humans during development of ageing process. Clin Chim Acta 1999;288(1-2):137–45.
45. Piers LS, Soars MJ, McCormack LM, et al. Is there evidence for an age-related reduction in metabolic rate? J Appl Phys 1998;85:2196–204.
46. Poehlman ET, Berke EM, Joseph JR, et al. Influence of aerobic capacity, body composition, and thyroid hormones on the age-related decline in resting metabolic rate. Metabolism 1992;41:915–21.
47. Magri F, Fioravanti CM, vignati G, et al. Thyroid function in old and very old healthy subjects. J Endocrinol Invest 2002;25(10):60–3.
48. 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.
49. Cizza G, Brady LS, Calogero AE, et al. Central hypothyroidism is associated with advanced age in male Fischer 344/n rats: in vivo and in vitro studies. Endocrinology 1992;131:2672–80.
50. 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.
51. Kaplan MM, Utiger RD. Iodothyronine metabolism in rate liver homogenates. J Clin Invest 1978;61:459-471.
52. Kaplan MM. Subcellular alterations causing reduced hepatic thyroxine 5’-monodeiodinase activity in fasted rats. Endocrinology 1979:104:58-64.
53. Portnay GI, O’Brien JT, Bush J, et al. The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J. Clin Endocrinol Metab 1974;39:191-194.
54. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, et al. Decreased serum thyrotropin induced by fasting. J. Clin Endocrinol Metab 1977; 45:560-568.
55. Carlson HE, Drenick EJ, Chopra IJ, Hershman JM. Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin and thyroid hormones in starved obese men. J Clin Endocrinol Metab 1977;45:707-713.
56. Vinik AI, Kalk W, McLaren JH, Paul M. Fasting blunts the TSH response to synthetic thyrotropinreleasing hormone (TRH). J Clin Endocrinol Metab 1975;40:509-511.
57. Azizi F. Effect of dietary composition of fasting induced changes in serum thyroid hormones and thyrotropin. Metab. Clin. Exp 1978;27:935-942.
58. Brayshaw ND, Brayshaw DD. Thyroid hypofunction in premenstrual syndrome. NEJM 1986;315(23):1486-7.
59. Girdler SS, Pedersen CA, Light CK. Thyroid axis function during the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology 1995;20(4):395-403.
60. Neek G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheum 1992;19(7):1120-1122.
61. Wikland B, Lowhagen T, Sandberg PO. Fine needle aspiration cytology of the thyroid in chronic fatigue. Lancet 2001:357:956-57.
62. Chopra IJ. A study of extrathyroidial conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro. Endocrinology 1977;101:453-463. Blocks T4 to T3 conversion
63. Kaplan MM. Thyroxine 5’-monodeiodination in rat anterior pituitary homogenates. Endocrinology 1980;106(2):567-76
64. Wartofsky L, BurmanKD. Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 1982;3:164–217.
65. Rothwell PM, Lawler PG 1995 Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med 23:78–83.
66. De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of the current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006;22:57-86.
67. 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:
68. 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.
69. 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. increased rt3 decrease t3 with steroids.
70. 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. increased reverse T3 with carbohydrate diet.
71. 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.
72. 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. 50% reduction in free t3 in diabetics.
73. 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.
74. 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.
75. Robin P. Peeters, Pieter J. Wouters, Hans van Toor, Ellen Kaptein, Theo J. Visser, and Greet Van den Berghe. 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. The Journal of Clinical Endocrinology & Metabolism 90(8):4559–4565.
76. Everts ME, De Jong M, Lim CF, Docter R, et al. Different regulation of thyroid hormone transport in liver and pituitary: Is possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man. Thyroid 1996;6(4):359-368. —increased T4 with NTI
77. Lim CF, Docter R, Visser, Drenning. Inhibition of thyroxine transport into cultured rathepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty. JCEM 1993;76(5):1165-1172.
78. Hennemann G, Vos R A, de Jong M, Krenning E P, Docter R. Decreased peripheral 3,5,3′-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues. JCEM 1993;77(5):1431-5.
79. De Jong M, Docter R, Bernard BF, van der Heijden JT, van Toor H. T4 uptake into the perfused rat liver and liver T4 uptake in humans are inhibited by fructose. Am J Physiol Endocrinol Metab 1994;266:E768-E775.
80. De Jong M, Docter R, Van Der Hoek HJ, et al. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131:463–70.
81. Hennemann G, Krenning EP. The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation. Best Practice & Research Clinical Endo& Metab 2007;21(2); 323–338.
82. Krenning EP, Docter R, Bernard B, Visser T, Hennemann G. Decreased transport of thyroxine (T4), 3,3′,5-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett. 1982 Apr 19;140(2):229-33.
83. Hennemann G, Krenning EP, Bernard B, Huvers F, Mol J, et al. Regulation of influx and efflux of thyroid hormones in rat hepatocytes: possible physiologic significance of the plasma membrane in the regulation of thyroid hormone activity. Horm Metab Res Suppl 1984;14:1-6.
84. FW Wassen, EP Moerings, H van Toor, G Hennemann, and ME Everts. Thyroid hormone uptake in cultured rat anterior pituitary cells: effects of energy status and bilirubin. J Endocrinology 2000;165:599-606. pituitary different transport not suppressed with decrease energy
85. 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.
86. Lowe J, Garrison R, Reichman A, MD, Yellin J, Thompson BA, Kaufman D. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled response-driven crossover study.: Clinical Bulletin of Myofascial Therapy, 2(2/3):31-58, 1997.
87. 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, 2(2/3):91-124, 1997.
88. Lowe JC ,Reichman AJ, Garrison R, Yellin J.. Triiodothyronine (T3) treatment of euthyroid fibromyalgia: a small-n replication of a double-blind placebo-controlled crossover study. Clinical Bulletin of Myofascial Therapy, 2(4):71-88, 1997.
89. Yellin BA, Reichman AJ, Lowe JC ,The process of Change During T3 Treatment for Euthyroid Fibomyalgia: A Doulbe-Blind Palcebo-Controlled Crossover Study. The Metabolic Treatment of Fibromyalgia. McDowell Publishing 2000.
90. Wikland B, Lowhagen T, Sandberg PO. Fine needle aspiration cytology of the thyroid in chronic fatigue. Lancet 2001:357:956-57.
91. Teitelbaum J, Bird B, Greenfield R, Weiss A, Muenz L, Gould L. Effective Treatment of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) – A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study. Journal of Chronic Fatigue Syndrome Volume 8, Issue 2 – 2001.
92. Gitlin M, Altshuler LL, Frye MA, Suri R, et al. Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors. J Psychiatry Neurosci 2004;29(5):383-386.
93. Krotkiewski M, Holm G, Shono N. Small doses of triiodothyronine can change some risk factors associated with abdominal obesity. International J Obesity 1997;21:922-929.
94. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry 2006; 163:1519–153.
95. Brayshaw ND, Brayshaw DD. Thyroid hypofunction in premenstrual syndrome NEJM 1986;315(23):1486-1487.
96. Abraham G, Milev R, Lawson JS. T3 augmentation of SSRI resistant depression. Journal of Affective Disorders 2006;91:211–215
97. 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. International Journal of Neuropsychopharmacology (2008), 11, 15–25.
98. Klein I, Danzi S. Thyroid Hormone Treatment to Mend a Broken Heart. J Clin Endocrinol Metab. April 2008;93(4):1172–1174.
99. Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, et al. Acute effects of triiodothyronine replacement therapy in patients with chronic heart failure and low-T3 syndrome: A randomized, placebo-controlled study. J Clin Endocrinol Metab 2008;93(4):1351-8.
100. 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
101. 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. Blocks thryoid receptor and suppresses D1
102. 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.reduced thyroid binding and activity
103. 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. decreased BMR with fasting and increased rT3 (decreased T4 to T3 coversion and metabolim
104. Pittman JA, Tingley JO, Nickerson JF, Hill SR. Antimetabolic activity of 3,3’,5’-triiodo-dl-thyronine in man 1960; Metabolism;9:293-5. reduced metabolism
105. Mitchell AM, Manley SW, Rowan KA, and Mortimer RH. Uptake of reverse T3 in the human choriocarcinoma cell line, JAr. Placenta 20: 65–70. Placenta 1999, 20, 65–70 inhibits uptake of T3 and T4 into the cell
106. Demers LM, Spencer CA. NACB: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease–Thyrotropin/Thyroid Stimulating Hormone (TSH). Academy of the American Association for Clinical Chemistry 2003.
107. Lecomte P, Lecureuil N, Lecureuil M, Salazar CO, Valat C. Age modulates effects of thyroid dysfunction on sex hormone binding globulin (SHBG) levels. Exp Clin Endocrinol 1995;103:339-342.
108. 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.
109. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM 1993 Association between serum interleukin-6 and serum 3,5,3_-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 77:1695–
110. 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 78: 288-291.
111. 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;71:1567-1572.
112. Coiro V, Passeri M, Capretti L, Speroni G. Serotonergic control of TSH and PRL secretion in obese men. Psychoneuroendocrinology 1990;15(4):261-268.
113. Donders S H; Pieters G F; Heevel J G; Ross H A; Smals A G; Kloppenborg P W. Disparity of thyrotropin (TSH) and prolactin responses to TSH-releasing hormone in obesity. JCEM;1985;61(1):56-9.
114. Ford M, Cameron E, Ratcliffe W, Horn DB, Toft AD, et al. TSH response to TRH in substantial obesity. Int J Obes 1980(4):121–125.
115. Meier C, Trittibach P, Guglielmetti M, Staub JJ, et al. Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ 2003;326(8):311-312.
116. 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.
117 Saunders J, Hall SHE, Sonksen PH. Thyroid hormones in insulin requiring diabetes before and after treatment. Diabetologia 1978;15:29-32.
118. Zulewski H, Muller B, Exer P, Miserez AR Staub JJ. Estimation of tissue hypothyroid by a new clinical score: Evaluaton of patients with various grades of hypothyroidism and controls. JCEM 1997;82:771-776