I present to you a near-exhaustive list of references on the usefulness of thyroid hormones in diverse age-related diseases. These come out of the Hormone Handbook by Thierry Hertoghe, MD (International Medical Books) and are presented here with permission by Hertoghe. Dr. Hertoghe of Belgium is one of Europe’s leading professional advocates of anti-aging medicine.

Senescence (the aging process in mature individuals) is associated with a decline of the thyroid axis

Reductions of TSH, T3 and T4 with senescence

1. Wiener R, Utiger RD, Lew R, Emerson CH. Age, sex, and serum thyrotropin concentrations in primary hypothyroidism. Acta Endocrinol (Copenh). 1991 Apr;124(4):364-9
2. Bermudez F, Surks MI, Oppenheimer JH. High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease. J Clin Endocrinol Metab. 1975 Jul;41(1):27-40
3. Hesch RD, Gatz J, Juppner H, Stubbe P. TBG-dependency of age related variations of thyroxine and triiodothyronine. Horm Metab Res. 1977 Mar;9(2):141-6
4. Herrmann J, Heinen E, Kroll HJ, Rudorff KH, Kruskemper HL. Thyroid function and thyroid hormone metabolism in elderly people. Low T3-syndrome in old age? Klin Wochenschr. 1981 Apr 1;59(7):315-23
5. Djordjevic MZ, Paunkovic ND, Djordjevic-Lalosevic VB, Paunkovic Dz S. The effect of age on in vitro thyroid function tests in adult patients on a chronic hemodialysis program. Srp Arh Celok Lek. 1990 Jul-Aug;118(7-8):291-3
6. Spaulding SW. Age and the thyroid. Endocrinol Metab Clin North Am. 1987 Dec;16(4):1013-25
14. Smeulers J, Visser TJ, Burger AK, Docter R, Hennemann G. Decreased triiodothyronine (T3) production in constant reverse T3 production in advanced age. Ned Tijdschr Geneeskd. 1979 Jan 6;123(1):12-5

Decrease of the metabolic clearance of thyroid hormones with age

7. Gregerman RI, Gaffney GW, Shock NW, Crowder SE. Thyroxine turnover in euthyroid man with special reference to changes with age. J Clin Invest. 1962 Nov;41:2065-74
8. Katzeff HL. Increasing age impairs the thyroid hormone response to overfeeding. Proc Soc Exp Biol Med. 1990 Jul;194(3):198-203

Reduction of the amount of thyroid hormone (cellular) receptors with age

9. Kvetny J. Nuclear thyroxine and triiodothyronine binding in mononuclear cells in dependence of age. Horm Metab Res. 1985 Jan;17(1):35-8

Alteration of the circadian cycle of serum TSH with age: reduced amplitude and phase advance

10. Greenspan SL, Klibanski A, Rowe JW, Elahi D. Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation. Am J Physiol. 1991 Mar;260(3 Pt 1):E486-91
11. Barreca T, Franceschini R, Messina V, Bottaro L, Rolandi E. 24-hour thyroid-stimulating hormone secretory pattern in elderly men. Gerontology. 1985;31(2):119-23

Thyroid hormones may oppose and thyroid hormones deficiency may trigger several mechanisms of senescence

Excessive free radical formation: thyroid hormones stimulate antioxidant activity

12. Antipenko AYe, Antipenko YN. Thyroid hormones and regulation of cell reliability systems. Adv Enzyme Regul. 1994;34:173-98
13. Tseng YL, Latham KR. Iodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation. Lipids. 1984 Feb;19(2):96-102
14. Bozhko AP, Gorodetskaia IV. The role of thyroid hormones in prevention of disorders of myocardial contractile function and antioxidant activity during heat stress. Ross Fiziol Zh Im I M Sechenova. 1998 Mar;84(3):226-32
15. Faure P, Oziol L, Artur Y, Chomard P. Thyroid hormone (T3) and its acetic derivative (TA3) protect low-density lipoproteins from oxidation by different mechanisms. Biochimie. 2004 Jun;86(6):411-8
16. Brzezinska-Slebodzinska E. Influence of hypothyroidism on lipid peroxidation, erythrocyte resistance and antioxidant plasma properties in rabbits. Acta Vet Hung. 2003;51(3):343-51
17. Oziol L, Faure P, Bertrand N, Chomard P. Inhibition of in vitro macrophage-induced low density lipoprotein oxidation by thyroid compounds. J Endocrinol. 2003 Apr;177(1):137-46

Imbalanced apoptosis: TSH inhibits undesirable apotosis

18. Feldkamp J, Pascher E, Perniok A, Scherbaum WA. Fas-Mediated apoptosis is inhibited by TSH and iodine in moderate concentrations in primary human thyrocytes in vitro. Horm Metab Res. 1999 Jun;31(6):355-8.

Malaborption of important nutrients: thyroid hormones improve macronutrient uptake

19.Misra GC, Bose SL Samal AK. Malabsorption in thyroid dysfunctions. J Indian Med Assoc. 1991 Jul;89(7):195-7

Failure of repair systems: thyroid hormones reduce damage and accelerate repair

20. Palmer KC, Mari F, Malian MS. Cadmium-induced acute lung injury: compromised repair response following thyroidectomy. Environ Res. 1986 Dec;41(2):568-84
21. Safer JD, Crawford TM, Holick MF. A role for thyroid hormone in wound healing through keratin gene expression. Endocrinology. 2004 May;145(5):2357-61

Immune deficiency: stimulates the immune system

Low thyroid hormone levels are associated with immune deficiency

22. Kmiec Z, Mysliwska J, Rachon D, Kotlarz G, Sworczak K, Mysliwski A. Natural killer activity and thyroid hormone levels in young and elderly persons. Gerontology. 2001 Sep-Oct;47(5):282-8
23. Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F, Boschi F, Pratelli L, Pizzoferrato A, Piras F, Facchini A. Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians. Clin Exp Immunol. 1999 Apr;116(1):19-27
24. Basso A, Piantanelli L, Rossolini G, Piloni S, Vitali C, Masera N. Role of triiodothyronine in down-regulation and recovery of lymphocyte beta-adrenoceptors in thyroidectomized patients. J Clin Endocrinol Metab. 1991 Dec;73(6):1340-4
25. Chow CC, Mak TW, Chan CH, Cckram CS. Euthyroid sick syndrome in pulmonary tuberculosis before and after treatment. Ann Clin Biochem. 1995 Jul; 32 (Pt 4): 385-91

Thyroid treatment improves the immune defences

26. Padberg S, Heller K, Usadel KH, Schumm-Draeger PM. One-year prophylactic treatment of euthyroid Hashimoto’s thyroiditis patients with levothyroxine: is there a benefit? Thyroid. 2001 Mar;11(3):249-55
27. Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaagaoglu E, Yetgin S, Kansu E, Gedik O. Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto’s thyroiditis. Endocr J. 2005 Jun;52(3):337-43
28. Bloehr H, Bregengaard C, Povlsen JV. Triiodothyronine stimulates growth of peripheral blood mononuclear cells in serum-free cultures in uremic patients. Am J Nephrol. 1992;12(3):148-54
Paavonen T. Enhancement of human B lymphocyte differentiation in vitro by thyroid hormone. Scand J Immunol. 1982 Feb;15(2):211-5
29. Botella-Carretero JI, Prados A, Manzano L, Montero MT, Escribano L, Sancho J, Escobar-Morreale HF. The effects of thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with differentiated thyroid carcinoma before and during thyroxine withdrawal. Eur J Endocrinol. 2005 Aug;153(2):223-30
30. Balazs C, Leovey A, Szabo M, Bako G. Stimulating effect of triiodothyronine on cell-mediated immunity. Eur J Clin Pharmacol. 1980 Jan;17(1):19-23
31. Fabris N, Mocchegiani E, Mariotti S, Pacini F, Pinchera A. Thyroid function modulates thymic endocrine activity. J Clin Endocrinol Metab. 1986 Mar;62(3):474-8
32. Dorshkind K, Horseman ND. The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency. Endocr Rev. 2000 Jun;21(3):292-312
33. Kvetny J, Matzen LE. Thyroid hormone induced oxygen consumption and glucose-uptake in human mononuclear cells. Thyroidology. 1989 Apr;1(1):5-9
34. McCormack PD, Thomas J, Malik M, Staschen CM. Cold stress, reverse T3 and lymphocyte function. Alaska Med. 1998 Jul-Sep;40(3):55-62

Limits to healthy cell proliferation: stimulates fibroblast proliferation and differentiation

35. Ahsan MK, Urano Y, Kato S, Oura H, Arase S. Immunohistochemical localization of thyroid hormone nuclear receptors in human hair follicles and in vitro effect of L-triiodothyronine on cultured cells of hair follicles and skin. J Med Invest. 1998 Feb;44(3-4):179-84

Poor gene polymorphisms: poor thyroid gene polymorphisms may increase the risk of age-related diseases, and thyroid dysfunction may increase the risk of phenotypic expression of other unfavourable gene polymorphisms

36. Hustad S, Nedrebo BG, Ueland PM, Schneede J, Vollset SE, Ulvik A, Lien EA. Phenotypic expression of the methylenetetrahydrofolate reductase 677C–>T polymorphism and flavin cofactor availability in thyroid dysfunction. Am J Clin Nutr. 2004 Oct;80(4):1050-7
37. Silva JM, Dominguez G, Gonzalez-Sancho JM, Garcia JM, Silva J, Garcia-Andrade C, Navarro A, Munoz A, Bonilla F. Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene. 2002 Jun 20;21(27):4307-16

Thyroid hormones and psychic well-being

Lower quality of life and fatigue: the association with lower thyroid hormone levels

38. Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, Dore CJ, Finer N, Naoumova P. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002 Apr 1;112(5):348-54
39. Guimaraes V, DeGroot LJ. Moderate hypothyroidism in preparation for whole body 131I scintiscans and thyroglobulin testing. Thyroid. 1996 Apr;6(2):69-73
40. Heitman B, Irizarry A. Hypothyroidism: common complaints, perplexing diagnosis. Nurse Pract. 1995 Mar;20(3):54-60
41. Doucet J, Trivalle C, Chassagne P, Perol MB, Vuillermet P, Manchon ND, Menard,JF, Bercoff E. Does age play a role in clinical presentation of hypothyroidism? J Am Geriatr Soc. 1994 Sep;42(9):984-6
42. De Lorenzo F, Xiao H, Mukherjee M, Harcup J, Suleiman S, Kadziola Z, Kakkar VV. Chronic fatigue syndrome: physical and cardiovascular deconditioning. QJM. 1998 Jul;91(7):475-81

Lower quality of life and fatigue: the improvement with thyroid treatment

43. Dzurec LC. Experiences of fatigue and depression before and after low-dose L-thyroxine supplementation in essentially euthyroid individuals. Res Nurs Health. 1997 Oct;20(5):389-98
44. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999 Feb 11;340(6):424-9
45. Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine, Ed. German Society of Anti-Aging Medicine-Verlag 2003- 2004; 32-43
46. Hashizume K. Supplement with target hormone in aged patients with endocrine dysfunction: thyroid hormone replacement therapy. Nippon Ronen Igakkai Zasshi. 2000 Nov;37(11):870-2.
47. Surkov SI, Naarov AN, Kotova GA, Artemova AM. The efficacy of replacement therapy with L-thyroxine in manifest and latent forms of hypothyroidism. Probl Endokrinol (Mosk). 1990 Sep-Oct;36(5):14-8.

Depression: the association with lower thyroid hormone levels

48. Pop VJ, Maartens LH, Leusink G, van Son MJ, Knottnerus AA, Ward AM, Metcalfe R, Weetman AP. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998 Sep;83(9):3194-7
49. Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Subclinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry. 1993 Mar;150(3):508-10
50. Gold MS, Pottash AL, Extein I. “Symptomless” autoimmune thyroiditis in depression. Psychiatry Res. 1982 Jun;6(3):261-9
51. O’Shanick GJ, Ellinwood EH Jr. Persistent elevation of thyroid-stimulating hormone in women with bipolar affective disorder. Am J Psychiatry. 1982 Apr;139(4):513-4
52. Howland RH. Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. J Clin Psychiatry. 1993 Feb;54(2):47-54
53. Kirkegaard C, Norlem N, Lauridsen UB, Bjorum N, Christiansen C. Protirelin stimulation test and thyroid function during treatment of depression. Arch Gen Psychiatry. 1975 Sep;32(9):1115-8
54. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder. I. Association with grade I hypothyroidism. Arch Gen Psychiatry. 1990 May;47(5):427-32
55. Haggerty JJ Jr, Evans DL, Golden RN, Pedersen CA, Simon JS, Nemeroff CB. The presence of antithyroid antibodies in patients with affective and nonaffective psychiatric disorders. Biol Psychiatry. 1990 Jan 1;27(1):51-60
56. Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF, Kupfer DJ, Frank E. Slower treatment response in bipolar depression predicted by lower pre-treatment thyroid function. Am J Psychiatry. 2002 Jan;159(1):116-21
57. Joffe RT, Marriott M. Thyroid hormone levels and recurrence of major depression. Am J Psychiatry. 2000 Oct;157(10):1689-91 (time to recurrence of major depression was inversely related to T3 levels but not to T4 levels)

Depression: the improvement with thyroid treatment

58. Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990 May;47(5):435-40
59. Afflelou S, Auriacombe M, Cazenave M, Chartres JP, Tignol J. Administration of high dose levothyroxine in treatment of rapid cycling bipolar disorders. Review of the literature and initial therapeutic application apropos of 6 cases. Encephale. 1997 May-Jun;23(3):209-17
60. Bauer M, Baur H, Berghofer A, Strohle A, Hellweg R, Muller-Oerlinghausen B, Baumgartner A. Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. J Affect Disord. 2002 Apr;68(2-3):285-94
61. Schwarcz G, Halaris A, Baxter L, Escobar J, Thompson M, Young M. Normal thyroid function in desipramine nonresponders converted to responders by the addition of L-triiodothyronine. Am J Psychiatry. 1984 Dec;141(12):1614-6
62. Prange AJ Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid. 1996 Oct;6(5):537-43
63. Birkenhager TK, Vegt M, Nolen WA. An open study of triiodothyronine augmentation of tricyclic antidepressants in inpatients with refractory depression. Pharmacopsychiatry. 1997 Jan;30(1):23-6
64. Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry. 1993 May;50(5):387-93
65. Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001 Oct;158(10):1617-22

Anxiety: the association with lower thyroid hormone levels

66. Kikuchi M, Komuro R, Oka H, Kidani T, Hanaoka A, Koshino Y. Relationship between anxiety and thyroid function in patients with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):77-81
67. Bauer M, Priebe S, Kurten I, Graf KJ, Baumgartner A. Psychological and endocrine abnormalities in refugees from East Germany: Part I. Prolonged stress, psychopathology, and hypothalamic-pituitary-thyroid axis activity. Psychiatry Res. 1994 Jan;51(1):61-73
68. Magliozzi JR, Maddock RJ, Gold AS, Gietzen DW. Relationships between thyroid indices and symptoms of anxiety in depressed outpatients Ann Clin Psychiatry. 1993 Jun;5(2):111-6
69 Sait Gonen M, Kisakol G, Savas Cilli A, Dikbas O, Gungor K, Inal A, Kaya A. Assessment of anxiety in subclinical thyroid disorders. Endocr J. 2004 Jun;51(3):311-5
70. Larisch R, Kley K, Nikolaus S, Sitte W, Franz M, Hautzel H, Tress W, Muller HW.. Depression and anxiety in different thyroid function states. Horm Metab Res. 2004 Sep;36(9):650-3
71. Constant EL, Adam S, Seron X, Bruyer R, Seghers A, Daumerie C. Anxiety and depression, attention, and executive functions in hypothyroidism. J Int Neuropsychol Soc. 2005 Sep;11(5):535-44

Anxiety: the improvement with thyroid treatment

72. Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab. 2005 Feb;90(2):805-12
73. Venero C, Guadano-Ferraz A, Herrero AI, Nordstrom K, Manzano J, de Escobar GM, Bernal J, Vennstrom B. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev. 2005 Sep 15;19(18):2152-63

Memory loss and Alzheimer’s disease: the association with lower thyroid hormone levels

74. Nakanishi T. Consideration on serum triiodothyronine (T3), thyroxine (T4) concentration and T3/T4 ratio in the patients of senile dementia – is it possible to prevent cerebro-vascular dementia? Igaku Kenkyu. 1990 Feb;60(1):18-25
75. Ichibangase A, Nishikawa M, Iwasaka T, Kobayashi T, Inada M. Relation between thyroid and cardiac functions and the geriatric rating scale. Acta Neurol Scand. 1990 Jun;81(6):491-8
76. Molchan SE, Lawlor BA, Hill JL, Mellow AM, Davis CL, Martinez R, Sunderland T. The TRH stimulation test in Alzheimer’s disease and major depression: relationship to clinical and CSF measures. Biol Psychiatry. 1991 Sep 15;30(6):567-76
77. Burmeister LA, Ganguli M, Dodge HH, Toczek T, DeKosky ST, Nebes RD. Hypothyroidism and cognition: preliminary evidence for a specific defect in memory. Thyroid. 2001 Dec;11(12):1177-85
78. Monzani F, Pruneti CA, De Negri F, Simoncini M, Neri S, Di Bello V, Baracchini Muratorio G, Baschieri L. Preclinical hypothyroidism: early involvement of memory function, behavioural responsiveness and myocardial contractility. Minerva Endocrinol. 1991 Jul-Sep;16(3):113-8
Istituto di Clinica Medica II, Universita di Pisa.
Baldini IM, Vita A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35
Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry. 1996 Oct 15;40(8):714-25

Memory loss and Alzheimer’s disease: the improvement with thyroid treatment

79. Monzon Monguilod MJ, Perez Lopez-Fraile I. Subclinical hypothyroidism as a cause of reversible cognitive deterioration. Neurologia. 1996 Nov;11(9):353-6
80. Kinuya S, Michigishi T, Tonami N, Aburano T, Tsuji S, Hashimoto T. Reversible cerebral hypoperfusion observed with Tc-99m HMPAO SPECT in reversible dementia caused by hypothyroidism. Clin Nucl Med. 1999 Sep;24(9):666-8
Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993 May;71(5):367-71
Baldini IM, Vita A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35

Sleep disorders: the improvement with thyroid treatment

81. Ruiz-Primo E, Jurado JL, Solis H, Maisterrena JA, Fernandez-Guardiola A, Valverde C. Polysomnographic effects of thyroid hormones primary myxedema. Electroencephalogr Clin Neurophysiol. 1982 May;53(5):559-64
82. Orr WC, Males JL, Imes NK. Myxedema and obstructive sleep apnea. Am J Med. 1981 May;70(5):1061-6
83. Rajagopal KR, Abbrecht PH, Derderian SS, Pickett C, Hofeldt F, Tellis CJ, Zwillich CW. Obstructive sleep apnea in hypothyroidism. Ann Intern Med. 1984 Oct;101(4):491-4

Fertility:
Infertility: the association with lower thyroid hormone levels

Bispink L, Brandle W, Lindner C, Bettendorf G. Preclinical hypothyroidism and disorders of ovarian function. Geburtshilfe Frauenheilkd. 1989 Oct;49(10):881-8

Thyroid hormones and age-related diseases

Hypercholesterolemia: the association with lower thyroid hormone levels

Elder J, McLelland A, O’Reilly DS, Packard CJ, Series JJ, Shepherd J. The relationship between serum cholesterol and serum thyrotropin, thyroxine and tri-iodothyronine concentrations in suspected hypothyroidism. Ann Clin Biochem. 1990 Mar;27 ( Pt 2):110-3
Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. 1997 Oct;82(10):3421-4

Hypercholesterolemia: the improvement with thyroid treatment

Wiseman SA, Carter G, Alaghband Zadeh J, Fowler PB, Greenhalgh RM. Can thyroxine halt the progression of peripheral arterial disease? Eur J Vasc Surg. 1989 Feb;3(1):85-7
Franklyn JA, Daykin J, Betteridge J, Hughes EA, Holder R, Jones SR, Sheppard MC. Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol (Oxf). 1993 May;38(5):453-9
Selenkow HA, Wool MS. A new synthetic hormone combination for clinical therapy. Ann Int Med. 1967 July, 67 (1): 90-9
Alley RA, Danowski TS, Robbins TJ, Weir TF, Sabeh G, Moses CL. Indices during administration of T4 and T3 to euthyroid adults. Metabolism. 1968 Feb;17(2):97-104
Becerra A, Bellido D, Luengo A, Piedrola G, De Luis DA. Lipoprotein(a) and other lipoproteins in hypothyroid patients before and after thyroid replacement therapy. Clin Nutr. 1999 Oct;18(5):319-22
Mishkel MA, Crowther SM.Hypothyroidism, an important cause of reversible hyperlipidemia. Clin Chim Acta. 1977 Jan 17;74(2):139-51

Atherosclerosis: the association with lower thyroid hormone levels

90. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokoyama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004 Jul;89(7):3365-70
91. Myasnikov AL, Myasnikov LA, Zaitzev VF. The influence of thyroid hormones on cholesterol metabolism in experimental atherosclerosis in rabbits. J Atheroscler Res. 1963 Jul-Aug;37:295-300

Atherosclerosis: the improvement with thyroid treatment

92. Papaioannou GI, Lagasse M, Mather JF, Thompson PD. Treating hypothyroidism improves endothelial function. Metabolism. 2004 Mar;53(3):278-9
93. Nagasaki T, Inaba M, Henmi Y, Kumeda Y, Ueda M, Tahara H, Sugiguchi S, Fujiwara S, Emoto M, Ishimura E, Onoda N, Ishikawa T, Nishizawa Y. D ecrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function. Clin Endocrinol (Oxf). 2003 Nov;59(5):607-12 Myasnikov AL, Myasnikov LA, Zaitzev VF. The influence of thyroid hormones on cholesterol metabolism in experimental atherosclerosis in rabbits. J Atheroscler Res. 1963 Jul-Aug;37:295-300

Arterial hypertension: the association with lower thyroid hormone levels

94. Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine. 2004 Jun;24(1):1-13
95. Streeten DH, Anderson GH Jr, Howland T, Chiang R, Smulyan H. Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension. Hypertension. 1988 Jan;11(1):78-83
96. Fommei E, Iervasi G. The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans. J Clin Endocrinol Metab. 2002 May;87(5):1996-2000
97. Saito I, Ito K, Saruta T. Hypothyroidism as a cause of hypertension. Hypertension. 1983 Jan-Feb;5(1):112-5

Arterial hypertension: the improvement with thyroid treatment

98. Fuller H Jr, Spittell JA Jr, McConahey WM, Schirger A. Myxedema and hypertension. Postgrad Med. 1966 Oct;40(4):425-8
Gasiorowski W, Plazinska MT. Arterial hypertension associated with hyper and hypothyroidism. Pol Tyg Lek. 1992 Nov 2-9;47(44-45):1009-10
Oddzialu Terapii Izotopowej Zakladu Medycyny Nuklearnej CSK MSW, Warszawie.

Coronary heart disease: the association with lower thyroid hormone levels

99. Miura S, Iitaka M, Suzuki S, Fukasawa N, Kitahama S, Kawakami Y, Sakatsume Y, Yamanaka K, Kawasaki S, Kinoshita S, Katayama S, Shibosawa T, Ishii J. Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endocr J. 1996 Dec;43(6):657-63

Coronary heart disease and other cardiac diseases: the improvement with thyroid treatment

100. Barnes BO. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancet. 1959 Aug 22;2:149-52
101. Holland FW 2nd, Brown PS Jr, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg. 1992 Aug;54(2):301-5
102. Facktor MA, Mayor GH, Nachreiner RF, D’Alecy LG. Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs. Resuscitation. 1993 Oct;26(2):141-62
103. Israel M. An effective therapeutic approach to the control of atherosclerosis illustrating harmlessness of prolonged use of thyroid hormone in coronary disease. Am J Dig Dis. 1955 June;161-8

Cardiovascular disease and mortality: increased in hypothyroidism (+ 70 % for both)
Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216
Department of Internal Medicine B, Ernst-Moritz-Arndt-University, Greifswald, Germany

Stroke and other cerebrovascular disorders: the association with lower thyroid hormone levels

104. Hu R. Changes in serum thyroid hormones in acute cerebrovascular apoplexy and their clinical significance. Zhonghua Shen Jing Jing Shen Ke Za Zhi. 1990 Apr;23(2):87-9, 126
105. Benvenga S, Morgante L, Bartalena L, Manna L, Li Calzi L, Coraci MA, Trimarchi F. Serum thyroid hormones and thyroid hormone binding proteins in patients with completed stroke. Ann Clin Res. 1986;18(4):203-7

Obesity: the association with lower thyroid hormone levels

106. Resta O, Pannacciulli N, Di Gioia G, Stefano A, Barbaro MP, De Pergola G. High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing. Nutr Metab Cardiovasc Dis. 2004 Oct;14(5):248-53
107. Jung CH, Sung KC, Shin HS, Rhee EJ, Lee WY, Kim BS, Kang JH, Kim H, Kim SW, Lee MH, Park JR, Kim SW. Thyroid dysfunction and their relation to cardiovascular risk factors such as lipid profile, hsCRP, and waist hip ratio in Korea. Korean J Intern Med. 2003 Sep;18(3):146-53
108. Rimm AA, Werner LH, Yserloo BV, Bernstein RA. Relationship of ovesity and disease in 73,532 weight-conscious women. Public Health Rep. 1975 Jan-Feb;90(1):44-54

Obesity: the improvement with thyroid treatment

109. Moore R, Grant AM, Howard AN, Mills IH. Treatment of obesity with triiodothyronine and a very-low-calorie liquid formula diet. Lancet. 1980 Feb 2;1(8162):223-6
110. Gelvin EP, Kenigsberg S, Boyd LJ. Results of addition of liothyronine to a weight-reducing regimen.J Am Med Assoc. 1959 Jul 25;170(13):1507-12
111. Rozen R, Abraham G, Falcou R, Apfelbaum M. Effects of a ‘physiological’ dose of triiodothyronine on obese subjects during a protein-sparing diet. Int J Obes. 1986;10(4):303-12
112. Pasquali R, Baraldi G, Biso P, Piazzi S, Patrono D, Capelli M, Melchionda N. Effect of ‘physiological’ doses of triiodothyronine replacement on the hormonal and metabolic adaptation to short-term semistarvation and to low-calorie diet in obese patients. Clin Endocrinol (Oxf). 1984 Oct;21(4):357-67
113. Koppeschaar HP, Meinders AE, Schwarz F. Metabolic responses in grossly obese subjects treated with a very-low-calorie diet with and without triiodothyronine treatment. Int J Obes. 1983;7(2):133-41
114. Koppeschaar HP, Meinders AE, Schwarz F. The effect of a low-calorie diet alone and in combination with triiodothyronine therapy on weight loss and hypophyseal thyroid function in obesity. Int J Obes. 1983;7(2):123-31
115. Wilson JH, Lamberts SW. The effect of triiodothyronine on weight loss and nitrogen balance of obese patients on a very-low-calorie liquid-formula diet. Int J Obes. 1981;5(3):279-82
116. Moore R, Mehrishi JN, Verdoorn C, Mills IH. The role of T3 and its receptor in efficient metabolisers receiving very-low-calorie diets. Int J Obes. 1981;5(3):283-6
117. Moore R, Grant AM, Howard AN, Mills IH. Treatment of obesity with triioidothyronine and a very low caorie liquid formula diet. Lancet 1980 Feb. 2;223-6

Diabetes: The association with lower thyroid hormone levels

118. Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med. 1995 Jul;12(7):622-7
119. Alvarez-Marfany M, Roman SH, Drexler AJ, Robertson C, Stagnaro-Green A. Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin Endocrinol Metab. 1994 Jul;79(1):10-6
120. Lamberg; B-A. Glucose metabolism in thyroid disease. Acta Med Scand. 1965178: 351
121. ELRICK H, HLAD CJ Jr, ARAI Y. Influence of thyroid function on carbohydrate metabolism and a new method for assessing response to insulin. J Clin Endocrinol Metab. 1961 Apr;21:387-400

Diabetes: the improvement with thyroid treatment

122. Houssay BA. The thyroid and diabetes. Vitam Horm. 1946;4:188
123. Eaton CD. Coexistence of hypothyroidism with diabetes mellitus. J Mich State Med Soc. 1954 Oct;53(10, Part 1):1101

Rheumatism: the association with lower thyroid hormone levels

124. Herrmann F, Hambsch K, Sorger D, Hantzschel H, Muller P, Nagel I. Low T3 syndrome and chronic inflammatory rheumatism. Z Gesamte Inn Med. 1989 Sep 1;44(17):513-8
538. Shiroky JB, Cohen M, Ballachey ML, Neville C. Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey. Ann Rheum Dis. 1993 Jun;52(6):454-6
539. Neeck G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheumatol. 1992 Jul;19(7):1120-2
540. Magaro M, Zoli A, Altomonte L, Mirone L, La Sala L, Barini A, Scuderi F. The association of silent thyroiditis with active systemic lupus erythematosus. Clin Exp Rheumatol. 1992 Jan-Feb;10(1):67-70

Rheumatism: the improvement with thyroid treatment

1032. Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on musculoskeletal symptoms. Clin Rheumatol. 1993 Sep;12(3):341-5
1033. Gledhill RF, Dessein PH, Van der Merwe CA. Treatment of Raynaud’s phenomenon with triiodothyronine corrects co-existent autonomic dysfunction: preliminary findings. Postgrad Med J. 1992 Apr;68(798):263-7

Osteoporosis: the improvement with thyroid treatment

1065. Svanberg E, Healey J, Mascarenhas D. Anabolic effects of rhIGF-I/IGFBP-3 in vivo are influenced by thyroid status. Eur J Clin Invest. 2001 Apr;31(4):329-36.

Cancer: the association with lower thyroid hormone levels

619. Shelton BK. Hypothyroidism in cancer patients. Nurse Pract Forum. 1998 Sep;9(3):185-91
620. Mellemgaard A, From G, Jorgensen T, Johansen C, Olsen JH, Perrild H. Cancer risk in individuals with benign thyroid disorders. Thyroid. 1998 Sep;8(9):751-4
621. Liechty RD, Hodges RD, Burket J. Cancer and thyroid function. JAMA. 1963 Jan 5;183:30-2.
Tellini U, Pellizzari L, Pravadelli B. Thyroid function in elderly with neoplasms. Minerva Med. 1999 Apr;90(4):111-21
622. Shering SG, Zbar AP, Moriarty M, McDermott EW, O’Higgins NJ, Smyth PP. Thyroid disorders and breast cancer. Eur J Cancer Prev 1996 Dec;5(6):504-6

Cancer: the improvement with thyroid treatment?

1100. Schwartz SBS. The relationship of thyroid deficiency to cancer: a 50-year retrospective study. J IAPM, 1977, 6 (1):9-21
1101. Lacka K. Treatment with L-thyroxine for differentiated thyroid carcinoma. Wiad Lek. 2001;54 Suppl 1:368-72

Longevity: the association with thyroid hormone

660. Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-92
661. Iervasi G, G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low T3 syndrome: a strong predictor of death in patients with heart disease. Circulation. 2003; 107(5): 708-13
Kozdag G, Ural D, Vural A, Agacdiken A, Kahraman G, Sahin T, Ural E, Komsuoglu B. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy. Eur J Heart Fail. 2005 Jan;7(1):113-8
Department of Cardiology, Kocaeli University, Yahyakaptan Mah. A4 Blok Daire:3, Kocaeli 41050, Turkey. [email protected]
Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med. 2005 Feb;118(2):132-6
Institute of Clinical Physiology, C.N.R., Pisa, Italy. [email protected]

Thyroid Diagnosis:

Frequency of overt and subclinical hypothyroidism

1. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68
2. Wiersinga WM. Subclinical hypothyroidism and hyperthyroidism. I. Prevalence and clinical relevance. NethJofMed 1994;46:197-204

Serum thyroid tests

Ladenson PW. Optimal laboratory testing for diagnosis and monitoring of thyroid nodules, goiter, and thyroid cancer. Clin Chem. 1996 Jan;42(1):183-7
Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA. [email protected]

Serum TSH

Nunez S, Leclere J. Diagnosis of hypothyroidism in the adult. Rev Prat. 1998; 48(18): 1993-8.
van Coevorden A, Mockel J, Laurent E, Kerkhofs M, L’Hermite-Baleriaux M, Decoster C, Neve P, Van Cauter E. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991 Apr;260(4 Pt 1):E651-61
Greenspan SL, Klibanski A, Rowe JW, Elahi D. Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation. Am J Physiol. 1991 Mar;260(3 Pt 1):E486-91
Beth Israel Hospital, Boston
Hertoghe T. Poor Reliability of the single Plasma TSH-test for diagnosis of thyroid dysfunction and follow-up. Anti-Aging Medical Therapeutics, 2000, Ed. Klatz R & Goldman R, publication of the American Academy of Anti-Aging Medicine & Health Quest Publications, Marina del Rey, CA

Serum Thyroxine and Triiodothyronine

Zucchelli GC, Pilo A, Chiesa MR, Masini S. Systematic differences between commercial immunoassays for free thyroxine and free triiodothyronine in an external quality assessment program. Clin Chem. 1994 Oct;40(10):1956-61.
Soldin OP, Hilakivi-Clarke L, Weiderpass E, Soldin SJ. Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays. Clin Chim Acta. 2004 Nov;349(1-2):181-9.

Serum thyroid antibodies

Lian XL, Bai Y, Sun ML, Guo ZS, Dai WX. Clinical validity of anti-thyroperoxidase antibody and anti-thyroglobulin antibody. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004 Dec;26(6):677-81
Department of Endocrinology, PUMC Hospital, CAMS and PUMC, Beijing 100730, China. [email protected]
Engler H, Riesen WF, Keller B. Anti-thyroid peroxidase (anti-TPO) antibodies in thyroid diseases, non-thyroidal illness and controls. Clinical validity of a new commercial method for detection of anti-TPO (thyroid microsomal) autoantibodies. Clin Chim Acta. 1994 Mar;225(2):123-36
Institute of Clinical Chemistry and Haematology, St. Gallen, Switzerland
Caron P, Babin T, Oksman F, Hoff M. Anti-thyroid peroxidase in non-neoplastic thyroid pathology]
Rev Med Interne. 1991 Sep-Oct;12(5):335-8 (“Anti-thyroid peroxidase antibodies ..their level decreased during replacement therapy for hypothyroidism”)
Departement d’Endocrinologie et Maladies Metaboliques, CHU Rangueil, Toulouse, France.
39. Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med. 1990; 113:450-454.
Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaagaoglu E, Yetgin S, Kansu E, Gedik O. Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto’s thyroiditis. Endocr J. 2005 Jun;52(3):337-43 (After 15 months of L-thyroxine treatment, there was a significant increase in free T4 and a significant decrease in TSH and anti-thyroglobulin antibody anti-thyroid peroxidase antibody
Levels, and a decrease in thyroid volume, whereas an increase was detected in patients who were followed without treatment)
Section of Endocrinology and Metabolism, Department of Internal Medicine,
Hacettepe University, Ankara, Turkey.

Serum TRH test

Bindeballe W, Gutekunst R, Lahrtz H, Rabenhorst G, Schemmel K. Diagnosis and control of therapy of thyroid disorders by TRH-test. Med Klin. 1975 Mar 21;70(12):505-9

Chailurkit L, Rajatanavin R. Comparison of basal serum TSH concentration by immunoradiometric assay and TRH stimulation test in the diagnosis of thyroid dysfunction. J Med Assoc Thai. 1990 Jun;73(6):329-34
Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Ishihara T, Akamizu T, Sawada K, Ikekubo K, Mori T. Usefulness of the TRH-T3 test in the diagnosis of central hypothyroidism. Nippon Naibunpi Gakkai Zasshi. 1983 Aug 20;59(8):1131-7
Bottermann P, Glogger C, Henderkott U. Intravenous and oral TRH-stimulation test: comparison of the value of both tests concerning diagnosis and therapy of thyroid diseases. Med Klin. 1979 Oct 12;74(41):1485-91

24-hour urine Thyroid Hormones

1. Fraser WD, Biggart E, O’Reilly D St J, Gray H W, McKillop JH, Thomson JA. Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? Br Med J. 1986, 293: 808-10
2. Chan V, Landon J. Urinary thyroxine excretion as index of thyroid function. Lancet. 1972, (Jan 1) 7740: 4-6
3. Tal E , Sulman FG. Urinary thyroxine. Lancet. 1972, 1291
4. Chan V, Besser GM, Landon J, Ekins RP. Urinary triiodothyronine excretion as index of thyroid function. Lancet 1972, (Aug 5) 253-256
5. Chan V, Besser GM, Landon J. Effects of oestrogen on urinary thyroxine excretion. Br Med J. 1972, 4: 699-701
6. Rastogi GK, Sawhney, Sinha, Thomas, Devi. Serum and urinary levels of thyroid hormones in normal pregnancy. Obstet Gynecol. 1974, 2: 176-80
7. Rogowski P,Siersbaek-Nielsen K, Mölholm Hansen J. Urinary excretion of thyroxine in different thyroid states. Acta Endocrinol (Kopenh). 1978, 87: 525-34
8. Kolendorf K, Broch Môller B, Rogowski P. The influence of chronic renal failure on serum and urinary thyroid hormone levels. Acta Endocrinol (Kopenh). 1978, 89: 80-8
9. Ali Afrasiaki M, Dabir Vaziri N, Grant Gwinup, Mays M, Barton CH, Ness RL,Valenta LJ. Thyroid function in the nephrotic syndrome. Ann Int Med. 1979, 90, 335-8
10. Aizawa T, Yamada T, Tawata M, Shimizu T, Furuta S, Kiyosawa K, Yakata M. Thyroid hormone metabolism in patients with liver cirrhosis, as judged by urnary excretion of triiodothyronine. J Am Geriatrics Soc. 1980;28(11):485-91
11. Yoshida K, Sakurada T, Kaise K, Saito S, Yoshinaga K. Measurement of triiodothyronine in urine. Tohoku J Exp Med. 1980;132(4):389-95
12. Lopresti JS, Warren DW, Kaptein EM, Croxson MS, Nicoloff JT. Urinary immunoprecipitation method for estimation of thyroxine to triiodothyronine conversion in altered thyroid states. J Clin Endocrinol Metab. 1982;55( 4):666-70
13. Yoshida K, Sakurada T, Kaise K, Yamamoto M, Saito S, Yoshinaga K. Thyroid stimulation test with urinary T3 concentration as an index of thyroid response. Tohuku J Exp Med. 1983;139(3):271-7
14. Mirralles-Garcia JM, Mories-Alvarez MT, Reglero-Chillon A, Lanao JM, Corrales-Hernandez JJ, Garcia-Diez LC. Urinary kinetics of triiodothyronine and their modification with age. Horm Metab Res. 1985;17(7):366-9
15. Orden I, Pie, Juste, Marsella, Blasco. Thyroxine in unextracted urine. Acta Endocrinol (Kopenh). 1987;114:503-8
16. Faber J, Siersbaek-Nielsen K, Kirkegaard C. Renal handling of thyroxine, 3,5,3’- and 3,3’,5’-triiodothyronine, 3,3’-diiodothyronine in man. Acta Endocrinol (Kopenh). 1987;115:144-8
17. Orden I, Pie J, Juste MG, Giner A, Gomez ME, Escanero JF. Urinary triiodothyronine excretion. Rev Espan Fisiol. 1988;44 (2):179-84
18. Hertoghe J. The usefulness of evaluating the urinary excretion of triiodothyronine and thyroxine in the urines of 24 hours for diagnosis of thyroid dysfunction and follow-up of thyroid treatment. Conference in Antwerp, Belgium, March 1975
19. Baisier WV, Hertoghe J,Eeckhaut W. Thyroid insufficiency. Is TSH the only diagnostic tool? J Nutr Env Med. 2000; 10: 105-13
20. Baisier WV, Hertoghe J, Eeckhaut W. Thyroid insufficiency. Is thyroxine the only valuale drug? J Nutr Env Med. 2001;11:159-166
21. Hertoghe T. The efficacy of diagnosing borderline and overt hypothyroidism with the laboratory assessment of triiodothyronine and thyroxine excretion in the urines of 24 hours. A comparison with plasma thyroid tests. Optimal hormone therapy in the aging adult. Basic and advanced seminar, San Francisco, February, 2000

Corrective Thyroid Therapy

Thyroid medications

Alley RA, Danowski TS, Robbins TJ, Weir TF, Sabeh G, Moses CL Indices during administration of T4 and T3 to euthyroid adults. Metabolism. 1968 Feb;17(2):97-104 (equivalencies between T4, T3, T3 + T4, dessiccated thyroid preparations)

Thyroxine

48. Oppenheimer JH, Braverman LE, Toft A, Jackson, IM, Ladenson, PW. Thyroid hormone treatment when and what? J Clin Endocrinol Metab. 1995;80:2873-83
49. Dong BJ, Brown CH. Hypothyroidism resulting from generic levothyroxine failure. J Am Board Fam. Pract. l991;4:167-70
6. Roti E, Minelli R, Gardini E, Braverman LE. The use of misuse of thyroid hormone. Endocrine Rev. 1993;14:401-23
7. Toft AD. Thyroxine therapy. N Engl J Med. 1994 Jul 21;331(3):174-80
8. USP Dispensing Information: Volume 1- Drug Information for Health Care Professionals. The United States Pharmacopeial Convention, Rockville, MD, 1997
38. Ridgway EC, McCammon JA, Benotti J, Maloof F. Acute metabolic responses in myxedema to large doses of intravenous L-thyroxine. Ann Intern Med. 1972;77:549-55

Thyroxine-Triiodothyronine associations

Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism. 1977 Nov;26(11):1213-8
Mangieri CN, Lund MH. Potency of United States Pharmacopeia dessicated thyroid tablets as determined by the antigoitrogenic assay in rats. J Clin Endocrinol Metab. 1970 Jan;30(1):102-4
Gaby AR. Sub-laboratory hypothyroidism and the empirical use of Armour thyroid. Altern Med Rev. 2004 Jun;9(2):157-79
Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine (Ed. German Society of Anti-Aging Medicine-Verlag 2003) 2004; 32-43
Hertoghe T. Many conditions related to age reduce the conversion of thyroxine to triiodothyronine – a rationale for prescribing preferentially a combined T3 + T4 preparation in hypothyroid adults. Anti-Aging Medical Therapeutics 2000; IV: 138-53

Frequency of use of thyroid hormones

9. Kaufman SC, Gross GP, Kennedy DL. Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1997; 1:285-91
100. . Sawin CT, Geller A, Hershman JM, Castelli W, Bacharach P. The aging thyroid: the use of thyroid hormone in older persons. JAMA 1989;261:2653-5

Thyroid dosage

11. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med. 1987:316:764-70
47. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison ofthelhyrotrophin releasing hormone test using a sensitive thyrotropin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf). 1988:28:325-33
40. Grebe SK, Cooke RR, Ford HC, Fagerstrom JN, Cordwell DP, Lever NA, Purdie GL, Feek CM. Treatment of hypothyroidism with once weekly thyroxine. J Clin Endocrinol Metab. 1997 Mar;82(3):870-5
61. Kabadi UM. Optimal daily levothyroxine dose in primary hypothyroidism. Its relation to pre-treatment thyroid hormone indexes. Arch Intern Med. 1990;149:2209-12
62. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med. 1990:323:91-6
63. Kaplan MM. Monitoring thyroxine treatment during pregnancy. Thyroid. 1992:2:147-52
64. Singer PA. Thyroiditis acute, subacute, and chronic. Med Clin North Am. 1991:75:61-77
81. Banovac K, Carrington SAB, Levis S, Fill MD, Bilsker MS. Determination of replacement and suppressive doses ofthyroxine. J Intern Med Res. 1990; 18:210-8
35. Sawin CT, Herman T, Molitch ME, London MH, Kramer SM. Aging and the thyroid. Decreased requirement for chyroid hormone in older hypothyroid patients. Am J Med. 1983;75:206-9
36. Fisher DA. Management of congenital hypothyroidism. J Clin Endocrinol Metab 1991;72:523-9
37. Bearcoft CP, Toms GC, Williams SJ, Noonan K, Monson JP. Thyroxine replacement in post-radioiodine hypothyroidism. Clin Endocrinol. 1991;34:115-8

Thyroid hormone absorption and malabsorption

13. Hays MT, Nielsen KRK. Human thyroxine absorption: age effects and methodological analyses. Thyroid. 1994:4:55-64
14. Wenzel KW, Kirscheiper HE. Aspects of the absorption of oral 1-thyroxine in normal man. Metabolism. 1977;26:1-8
15. Benvenga S, Bartolone L, Squadrito S, Lo Giudice F, Trimarchi F. Delayed intestinal absorption of levothyroxine. Thyroid. 1995;5(4):249-53
16. Read DG, Hays MT, Hershman JM. Absorption of oral thyroxine in hypothyroid and normal man. J Clin Endocrinol Metab. 1970;30:798-9
17. Azizi F, Belur R, Albano J. Malabsorption of thyroid hormones after jejunoileal bypass for obesity. Ann Intern Med. 1979;90:941-2
18. Bevan JS, Munro JF. Thyroxine malabsorption following intestinal bypass surgery. Int J Obes. 1986; 10:245-6
19. Stone E, Leiter LA, Lambert JR, Silverberg JDH, Jeeyeebhoy KN, Burrow GN. L-Thyroxine absorption in patients with short bowel. J Clin Endocrinol Metab. 1984;59:139-41
20. Ain KB, Refetoff S, Fein HG, Weintraub BD. Pseudomalabsorption of levothyroxine. JAMA 1991;266:2118-20
21. Northcutt RC, Stiel JN, Hollifiels JW, Stant EG. The influence of cholestyramine on thyroxine absorption. JAMA. 1969;208:1857-61
22. Harmon SM, Siefert CF. Levothyroxine-cholestyramine interaction reemphasized. Ann Intern Med. 1991;115:658-9
23. Sperber AD, Liel Y. Evidence for interface with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med 1992; 152:183-4
24. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med. 1992;117:1010-3
25. Sherman SI, Tielens E, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. Am J Med. 1994;96:531-5
26. Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. J Clin Endocrinol Metab. 1996:80:857-9

Thyroid treatment: safety, special conditions to carefully watch for

67. Klein I, Ojamaa K. Thyroid hormone and the heart. Am J Med. 1996;101:459-60
68. Keating FR, Parkin TW, Selby JB, Dickinson LS. Treatment of heart disease associated with myxedema. Prog Cardiovasc Dis. 1960;3:364-81
69. Weinberg AD, Brennan MD, German CA, Marsh HM, O’Fallon WM. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med. 1983;143:893-897
70. Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med. 1984;77:261-6
Bauer M, Priebe S, Berghofer A, Bschor T, Kiesslinger U, Whybrow PC. Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders. J Affect Disord. 2001 Apr;64(1):35-42 (“Subjective response and side-effect tolerability of long-term supraphysiological doses (mean dose 368 µg/day for a mean of 54 months)of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention”)

Thyroid Treatment: side effects, complications

41. Paul TL, Kerrigan J, Kelly AM, Braverman LE, Baran DT. Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA. 1988;259:3137-41
42. Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients over treated with contemporary preparations. Ann Intern Med 1990; 105:11-5
43. Greenspan SL, Greenspan FS, Resnick NM, Block JE, Friedlander AL, Genant HK. Skeletal integrity in premenopausal and postmenopausal women receiving long-term L-thyroxine therapy Am J Med. 1991;91:5-14
44. Franklyn JA, Betteridge J, Daykin J, Holder R, Oates GD, Parle JV, et al. Long-term thyroxine treatment and bone mineral density. Lancet. 1992;340:9-13
45. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA. 1994;271:1245-9
46. Sawin CT, Geller A, Wolk PA, et al. Low serum thyrotropin concentration as a risk factor for atrial fibrillation in older persons. N Engi J Med. 1994;331:1249-52
79. Shibata H, Hayakawa H, Hirukawa M, Tadokoro K, Ogata E. Hypersensitivity caused by synthetic thyroid hormones in a hypothyroid patient with Hashimoto’s thyroiditis. Arch Intern Med. 1986; 146:1624-5
80. Magner J, Gerber P. Urticaria due to blue dye in synthroid tablets. Thyroid. 1994 Fall;4(3):341

Thyroid Treatment interferences or associations

33. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer. Ann Intern Med. 1994; 121:247-51
34. Rosenbaum RL, Barzel US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med. 1982:96:53-5
Mishell DR Jr, Colodny SZ, Swanson LA. The effect of an oral contraceptive on tests of thyroid function. Fertil Steril. 1969 Mar-Apr;20(2):335-9

Thyroid treatment follow-up

Fraser WD, Biggart EM, O’Reilly DS, Gray HW, McKillop JH, Thomson JA. Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? Br Med J (Clin Res Ed). 1986 Sep 27;293(6550): 293-808
39. Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med. 1990; 113:450-4
27. Browning MC, Bennet WM, Kirkaldy AJ, Jung RT. Intra-individual variation of thyroxine, triiodothyronine, and thyrotropin in treated hypothyroid patients: implications for monitoring replacement therapy. Clin Chem. 1988;34:696-9
28. Ain KB, Pucino F, Shiver TM, Banks SM. Thyroid hormone levels affected by time of blood sampling
in thyroxine-treated patients. Thyroid. 1993;3:81-5

TOPICS OF DISCUSSION

DISCUSSIONS ON THYROID DIAGNOSIS

SERUM TSH: IS THE TSH TEST SUFFICIENT FOR DIAGNOSIS AND FOLLOW-UP OF THYROID DEFICIENCY?

Claim: TSH is the first line test to do. It is sufficient to diagnose all forms of eu-, hypo- and hyperthyroidism. No other test is necessary for the diagnosis.

Facts: TSH is often insufficient on its own to diagnose between eu-, hypo- and hyperthyroidism, particularly to diagnose milder, borderline states of hypothyroidism. Other tests are necessary, as is a complete clinical evaluation (medical history, actual complaints, physical examination)

TSH: often considered as first line approach to diagnose thyroid dysfunction

Nunez S, Leclere J. Diagnosis of hypothyroidism in the adult. Rev Prat. 1998; 48(18): 1993-8.

Overreliance on laboratory tests without clinical evaluation may lead to considerable diagnostic errors

Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assay. J Clin Endocrinol Metab. 1990;71:553-8.
De Los Santos ET, Mazzaferri EL. Sensitive thyroid-stimulating hormone assays: Clinical applications and limitations. Compr Ther. 1988; 14(9): 26-33.
Becker DV, Bigos ST, Gaitan E, Morris JCrd, rallison ML, Spencer CA, Sugarawa M, Van Middlesworth L, Wartofsky L. Optimal use of blood tests for assessment of thyroid function. JAMA 1993 Jun 2; 269: 273 (“the decision to initiate therapy shoul be based on both clinical and laboratory findings and not solely on the results of a single laboratory test”)

Discussions and controversy in medical associations and journals on TSH reference range

Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228–38 (conclusions of a consensus panel of the Endocrine Society, the American Thyroid Association,and American Association of Clinical Endocrinology. Although the panel concluded that there was good data that patients with slight elevations of TSH above 4.5 may progress to overt hypothyroidism, and that levothyroxine therapy would prevent symptoms, they did not agree that early treatment provided any benefit!)
Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:581–5
Surks MI. Commentary: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586–7
Ringel MD, Mazzaferri EL. Editorial: subclinical thyroid dysfunction: can there be a consensus about the consensus? J Clin Endocrinol Metab. 2005;90:588–90
Pinchera A. Subclinical thyroid disease: to treat or not to treat? Thyroid. 2005;15:1–2

Data indicating a population mean value of 1.5 mU/liter for an iodine-sufficient population

6. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55–68
7. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
8. Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068–72
9. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
10. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003 Jan;13(1):3-126

Longitudinal studies indicating a rate of progression of mild thyroid failure into overt hypothyroidism of about 5% per year (50% or more in 10 years!)

6. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995; 43:55–68
11. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77–83
12. Huber G, Staub J-J, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221–6
13. Kabadi UM. ‘Subclinical hypothyroidism:’ natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957-61

Longitudinal study in diabetics : baseline TSH levels > 1.53 mU/liter predicted subsequent thyroid dysfunction, whereas no thyroid dysfunction if TSH levels < 1.53 mU/liter

25. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7

Assuring a reference interval for TSH that is more truly normal and should have a normal Gaussian distribution. The recommendation would be to draw upon a cohort of individuals with no personal or family history of thyroid dysfunction, no visible or palpable goiter, who are taking no medication, whose blood samples are drawn fasting in the morning hours (06–10 h), and who are seronegative for thyroid preoxidase antibodies. When data for subjects with positive antithyroid antibodies or a family history of autoimmune thyroid disease are excluded from a so-called normal cohort, the normal reference range becomes 0.4–2.5 mU/L(Demers & co, Baloch & co.)

9. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
10. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
10. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

Improved new reference range if persons with diffuse hypoechogenicity of the thyroid on ultrasound would be excluded in view of the recent finding that this precedes TPOAb positivity in autoimmune thyroid disease

26. Pedersen OM, Aardal NP, Larssen TB, Varhaug JE, Myking O, Vik-Mo H. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid. 2000;10:251–9

Revised reference TSH range of 0.3–3.0 mU/L of the American Association of Clinical Endocrinologists

27. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457–69

The value of a population-based reference range is limited when the individual patient-based reference range(i.e. their personal reference range) is narrow

28. Fraser CG, Harris EK. Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci. 1989;27:409–37
29. Harris EK. Effects of intra- and interindividual variation on the appropriate use of normal ranges. Clin Chem. 1974;20:1535–42

Individual TSH reference ranges are remarkably narrow within a relatively small segment of the population reference range, i.e. confined to only 25% of a range of 0.3–5.0 mU/liter.

A shift in the TSH value of the individual outside of his or her individual reference range, but still within the population reference range, would not be normal for that individual. For example, an individual (as in Anderson’s series) with a personal range of 0.5–1.0 mU/liter would be at subphysiological thyroid hormone levels at the population mean TSH of 1.5 mU/liter.

Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068–72

Studies of twins indicate that each of us has a genetically determined optimal free T4 (FT4)-TSH set point or relationship

9; Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
30. Meikle AW, Stringham JD, Woodward MG, Nelson JC. Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab. 1988 ; 66:588–92

A measured TSH difference of 0.75 mU/liter can already be significant in a patient. The NACB guideline 8 states that “.. the magnitude of difference in … TSH… values that would be clinically significant when monitoring a patient’s response to therapy… is 0.75 mU/liter. Greater TSH fluctuations in a specific patient may mean the patient becomes hypothyroid or hyperthyroid

11. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

Ethnic differences: the mean TSH level in African-Americans is 1.18 mU/liter, in contrast to a mean of 1.40 mU/liter in Caucasians, due to the greater frequency of autoimmune thyroid disease in whites (12.3%) than in blacks (4.3%), which may have unjustifiedly skewed the upper end of the TSH curve (NHANES data)

7. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–9

A study, which suggests that the a serum TSH cut-off point between hypo- and euthyroidism is 2, not 4 or 5.5 (Treating TPO antibody-positive hypercholesterolemic patients with TSH levels between 2-4 mU/L with low dose levothyroxine normalizes TSH levels and improves the lipid profile)

Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: Should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5

When data for subjects with positive TPOAb or a family history of autoimmune thyroid disease are excluded, the normal reference interval becomes much tighter, i.e. 0.4–2.0 mU/liter (7, 9) This tighter reference range may certainly be more applicable to African-Americans, who have a lower mean TSH

31. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
9. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40

Recognition of the need to tighten up the reference range for TSH has led to the National Academy of Clinical Biochemistry (NACB) reducing the upper limit of the reference range from 5.5 to 4.1 mU/L, but stating also that “greater than 95% of healthy, euthyroid subjects have a serum TSH concentration between 0.4 – 2.5 mU/L”. “.. patients with a serum TSH >2.5 mU/L, when confirmed by repeat TSH measurement made after 3 to 4 weeks, may be in the early stages of thyroid failure, especially if thyroid peroxidise antibodies are detected”

10. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

A serum TSH that rises in a given individual from a set point of 1.0 to 3.5 is likely to be abnormally elevated and imply early thyroid failure.

A minor change in serum free T4 results in an amplified change in TSH to outside of the usual population-based reference range, although the free T4 is still within its own population-based reference range, because of the the log-linear relationship between TSH and free T4.

In the case of subclinical hypothyroidism, for example, a slight drop in free T4 results in an amplified and inverse response in TSH secretion

31. Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260–5
32. Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44–50

There is a 3-fold difference between the average daily maximum (3) and minimum (1 mIU/ml)

89. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B,
Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9

TSH reference range is too large => need for narrower ranges

Pain RW. Simple modifications of three routine in vitro tests of thyroid function. Clin Chem. 1976; 22(10): 1715-8.
Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8
Frequency of abnormal TSH values
34. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
25. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7

The pituitary 5’-deiodinase type 2 that converts thyroxine into triiodothyronine (T3), is different than the liver and kidney 5’-deiodinase type 1 that provides the T3 for the rest of the body. This difference may explain why TSH secretion and thus serum TSH secreted by the pituitary gland may be normal, while the rest of the body may be in a thyroid deficient state.

1. Koenig RJ, Leonard JL, Senator D, Rappaport N, Watson A, Larsen PR. Regulation of thyroxine 5′-deiodinase activity by 3,5,3′-triiodothyronine in cultured anterior pituitary cells. Endocrinology. 1984 Jul;115(1):324-9.

In fasting, hypothyroidism or selenium deficiency for example, the 5‘-deiodinase of the pituitary gland increases or remains unchanged, while that of the liver decreases.

2. Suda AK, Pittman CS, Shimizu T, Cambers JB. The production and metabolism of 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine in normal and fasting subjects. J Clin Endocrinol Metab. 1978 Dec;47(6):1311-9
3. Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: Physiological and clinical implications. Endocr Rev. 1981 Winter;2(1):87-102.
4. Chanoine JP, Safran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord S, Arthur JR, Beckett GJ, Braverman LE Dubord S, Alex S, Arthur JR, Beckett GJ, Braverman LE, Leonard JLl. Selenium deficiency and type II 5′-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine. Endocrinology. 1992 Jul;131(1):479-84

A normal or low serum TSH may reflect in elderly persons hypothyroidism in peripheral tissues, and not anymore eu- or hyperthyroidism, because the pituitary gland has aged. Progressively with increasing age, the serum TSH test becomes less reliable as a diagnostic test.

5. Urban RJ. Neuroendocrinology of aging in the male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31.
Necessity for other tests than the TSH to diagnosis thyroid dysfunction, e.g. the serum free T4
6. Ladenson PW. Diagnosis of hypothyroidism. In Werner and Ingbar’s The Thyroid, 7th edition, Braverman LE and Utiger RE, Lippincott-Raven Publishers, Philadelphia. 1996; 878-82
7. Pacchiarotti A, Martino E, Bartalena L, Aghini Lombardi F, Grasso L, Buratti L, Falcone M, Pinchera A. Serum free thyroid hormones in subclinical hypothyroidism. J Endocrinol Invest. 1986 Aug;9(4):315-9
8. Surks MI, Chopra IJ, Mariosh CN, Nicoloff JT, Salomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA. 1990 Mar 16;263(11):1529-32
9. Davis JR, Black EG, Sheppard MC. Evaluation of a sensitive chemiluminescent assay for TSH in the follow-up of treated thyrotoxicosis. Clin Endocrinol Oxf. 1987; 27(5): 563-70

Serum thyroid hormone levels may not reflect the cellular thyroid status

10. Escobar del Rey F, Ruiz de Ona C, Bernal J, Obregon MJ, Morreale de Escobar G. Generalized deficiency of 3, 5, 3′-triiodothyronine in tissues from rats on a low iodine intake, despite normal circulating T3 levels. Acta Endocrinol (Copenh) 1989; 120: 490-8

Need to analyse valuable indicators of peripheral activity such as the serum levels of plasma binding proteins SHBG, TBG, CBG, or of thyroid-dependent enzymes such as alkaline phosphatase, osteocalcin

11. Smallridge RC. Metabolic, physiologic, and clinical indexes of thyroid function. In Werner and Ingbar’s The Thyroid, 7th edition, Braverman LE and Utiger RP, Lippincott-Raven Publishers, Philadelphia, 1996
12. Foldes J, Tarjan G, Banos C, Nemeth J, Varga F, Buki B. Biologic markers in blood reflecting thyroid hormone effect at peripheral tissue level in patients receiving levothyroxine replacement for hypothyroidism. Exp Clin Endocrinol. 1992; 99(3): 129-33

Serum TSH test for follow-up: The risk of misinterpretation increases when monitoring the treatment of hyper- or hypothyroidism

114. Talbot JN, Duron F, Feron R. Aubert P, Milhaud G. Thyroglobulin, thyrotropin and thyrotropin binding inhibiting immunoglobulins assayed at the withdrawal of antithyroid drug therapy as predictors of relapse of Graves’ disease within one year. J Endocrinol Invest. 1989; 12(9): 589-95

In 36-47 % of cinically euthyroid patients receiving adequate long-term thyroid therapy for hypothyroidism, an undetectable serum TSH is found

47. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994; 78(6): 1368-71
48. Gow SM, Caldwell G, Toft AD, Seth J, Hussey AJ, Sweeting VM, Beckett GJ. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metab. 1987; 64(2): 364-70

After intake of thyroidhormones , the serum TSH is transitorily depressed within 60 minutes and remains low for up to 9hours after intake

51. Chopra U, Carlson HE, Solomon DH. Comparison of inhibitory effects of 3,5,3′-triiodothyronine (T3), thyroxine (T4), 3,3,’,5′-triiodothyronine (rT3,), and 3,3′-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro. Endocrinology. 1978;103(2):393-402

Some patents who exhibit reversion of an initially high TSH level back into the reference range, are found to subsequently develop mild thyroid failure

24. Calaciura F, Motta RM, Miscio G, Fichera G, Leonardi D, Carta A, Trichitta V, Tassi V, Sava L, Vigneri R. Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia. J Clin Endocrinol Metab. 2002;87:3209–14

Supporters of the recommendations of the consensus panel promote a target TSH range of 1.0–1.5 mU/liter in patients already receiving T4 therapy, whereas they refuse to accept TSH levels of 3–10 mU/liter as abnormal in patients not receiving T4 therapy.

10. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

The lower end of the normal or reference range for TSH lies between 0.2 and 0.4 mU/liter, as indicated by a number of clinical studies

10. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126
11. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83
25 Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7
34. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
49. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med. 1991;151:165–8
50. Hershman JM, Pekary AE, Berg L, Solomon DH, Sawin CT Serum thyrotropin and thyroid hormone levels in elderly and middle-aged euthyroid persons. J Am Geriatr Soc. 1993;41:823–8
51. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5

FACTORS that DEPRESS the serum TSH

Aging

Urban RJ. Neuroendocrinology of aging in the male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31
13. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med. 1991; 151(1): 165-8

Fasting

14. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff OA. Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab. 1977; 45: 560
15. Borst GC, Osburne RC, O’Brian JT, Georges LP, Burman KD. Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: A potential cause of misinterpretation of thyroid function tests in the critically ill. J Clin Endocrinol Metab. 1983 Aug;57(2):380-3
16. Campbell GA, Kurcz M, Marshall S, Meites J. Effects of starvation in rats on serum levels of follicle stimulating hormone, luteinizing hormone, thyrotropin, growth hormone and prolactin; response to LH-releasing hormone and thyrotropin-releasing hormone. Endocrinology. 1977; 100(2): 580-7
17. Opstad PK. The thyroid function in young men during prolonged physical stress and the effect of energy and sleep deprivation. Clin Endocrinol. 1984; 20: 657-69.

Strenuous physical exercise

18. Scanlon MF, Toft AD. Regulation of thyrotropin secretion. In Werner and Ingbar’s The Thyroid, 7th edition

Pregnancy (first trimester)

19. Braverman LE and Utiger RE, Lippincott-Raven Publisers, Philadelphia. 1996; 220-40.

Depression and anxiety disorders

Bartalena L, Placidi GF, Martino E, Falcone M, Pellegrini L, Dell’Osso L, Pacchiarotti A, Pinchera A. Nocturnal serum thyrotropin (TSH) surge and the TSH response to TSH-releasing hormone: dissociated behavior in untreated depressives. Clin Endocrinol Metab. 1990 Sep;71(3):650-5.
Instituto di Endocrinologia, University of Pisa, ItalyBartalena L, Placidi GH, Martino E,
20.
26. Rupprecht R, Rupprecht C, Rupprecht M, Noder M, Mahlstedt J. Triiodothyronine, thyroxine, and TSH response to dexamethasone in depressed patients and normal controls. Biol Psychiatry. 1989;25(1): 22-32.
27. Maeda K, Yoshimoto Y, Yamadori A. Blunted TSH and unaltered PRL responses to TRH following repeated administration of TRH in neurological patients: A replication of neuroendocrine features of major depression. Biol Psychiatry. 1993; 33(4): 277-83.
28. Duval F, Macher JP, Mokrani MC. Difference between evening and morning thyrotropin responses to protirelin in major depressive episode. Arch Gen Psychiatry. 1990; 47(5): 443-8.
29. Loosen PT, Prange AJ Jr. erum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J Psychiatry 1982; 139(4): 405-16.

Non-thyroidal diseases: diabetes mellitus, Cushing’s syndrome, renal failure, cancer, myocardial infarction, AIDS, post-traumatic syndromes, chronic alcoholic liver disease, other illnesses

30. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990; 46(8): 591-9
31. Alexander CM, Kaptein EM, Lum SMC, Spencer CA, Kumar K, Nicoloff JT. Pattern of recovery of thyroid hormone indices associated with treatment of diabetes mellitus. J Clin Endocrinol Metab. 1982; 54: 362-366
32. Andrade SF, Kanitz-Ml, Povoa H Jr. Study of thyrotropic reserve in diabetics of adult type. Acta-Biol Mod Ger 1977; 36(10): 1479-81
33. Gonzalez C, Montoya-E, Jolin T. Effect of streptozotocin diabetes on the hypothalamic pituitary thyroid axis in the rat. Endocrinology 1980; 107(6): 2099-103
34. Rossi GL, Bestetti GE, Tontis DK, Varini M. Reverse hemolytic plaque assay study of luteinizing and follicle-stimulating hormone and thyrotropin secretion in diabetic rat pituitary glands. Diabetes 1989; 38(10): 1301-6
35. Adriaanse R, Brabant G, Endert E, Wiersinga W. Pulsatile thyrotropin secretion in patients with Cushing’s syndrome. Metabolism. 1994 Jun;43(6):782-6
36. Beyer HK-, Schuster P, Pressler H. Studies on hypothalamic pituitary thyroid regulation in hemodialysis patients. Nuklearmedizin 1981;20(1):19-24
37. Kokei S, Inoue T, lino S. Serum free thyroid hormones and response of TSH to TRH in nonthyroidal illnesses. Nippon Naibunpi Gakkai Zasshi. 1986; 62(11): 1231-43
38. De Marinis L, Mancini A, Masala R, Torlontano M, Sandric S, Barbarino A. Evaluation of pituitary-thyroid axis response to acute myocardial infarct. J Endocrinol Invest. 1985; 8(6): 519-22
39. Rondanelli M, Solerte SG, Fioravanti M, Scevola K, et al. Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection. AIDS Res Hum Retroviruses. 1997; 13(14): 1243-9.
40. Wintemitz WW, Dzur JA. Pituitary failure secondary to head trauma. Case report. J Neurosurg. 1976; 44(4): 504-5
41. Dzur JA, Wintemitz WW. Posttraumatic hypopituitarism: Anterior pituitary insufficiency secondary to head trauma. South Med J. 1976; 69(10): 1377-9
42. Modigliani E, Periac P, Perret G, Hugues JN, Coste T. TRH response in 53 patients with chronic alcoholism. Ann Med Interne Paris. 1979; 130(5):297-302
43. Ekman AC, Vakkuri 0, Ekman M, Leppalusto J, Ruckonen A, Knip M. Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or protection in man. J Clin Endocrinol Metab. 1996; 81(7):2627-32
44. Bacci V, Schussler GC, Kaplan TB. The relationschip between serum triidothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab. 1982; 54:1229-35
45. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim CF, Tuxen DV, Topliss DJ, Stockigt JR. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab. 1986 Apr;62(4):717-22
46. Bermudez F, Sucks MI, Opperheimer JH. High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease. J Clin Endocrinol Metab. 1975; 41: 27-40.

Medications: thyroid therapy, estroprogestative birth control pills, progestogens, anti-infammatory agents (incl. glucocorticoids and aspirin), antidepressants, L-Dopa, bromocriptine, neuroleptica, anti-hypertensives, antiarrhythmics (amiodarone), hypolipemic agents, IGF-1, somatostatin, etc.

47. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab. 1994;78(6):1368-71
48. Gow SM, Caldwell G, Toft AD, Seth J, Hussey AJ, Sweeting VM, Beckett GJ. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metab. 1987;64(2):364-70
49. Custro N, Scafidi V Costanzo G, Corsello FP. Variations in the serum levels of thyroid hormones and TSH after intake of a dose of L-thyroxine in euthyroid subjects and in adequately treated hypothyroid patients. Bull Soc Ital Biol Sper. l989; 65(11):1045-52
50. England ML, Hershman JM. Serum TSH concentration as an aid to monitoring compliance with thyroid hormone therapy in hypothyroidism. Am J Med Sci. 1986 Nov;292(5):264-6
51. Chopra U, Carlson HE, Solomon DH. Comparison of inhibitory effects of 3,5,3′-triiodothyronine (T3), thyroxine (T4), 3,3,’,5′-triiodothyronine (rT3,), and 3,3′-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro. Endocrinology. 1978; 103(2): 393-402
52. Fraser WD, Biggart EM, O’Reilly DS, Gray HW, McKillop JH, Thomson JA. Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? Br Med J (Clin Res Ed). 1986 Sep 27;293(6550): 293-808
53. Cooper DS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1981 Dec;53(6):1238-42
54. Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metabol. 1974;39:923-7
55. Rey Stocker I, Zufferey MM, Lemarchand MT, Rais M. The sensibility of the hypophysis, the gonads and the thyroid before and after the administration of oral contraceptives. A resume. Pediatr Ann. 1981;10(12):15-20.
56. Lemarchand-Beraud T. Influence of estrogens on pituitary responsiveness to LHRH and TRH in human. Reymond M, Berthier C. Ann Endocrinol Paris. 1977; 38(6): 379-82.
57. El-Etreby MF, Graf KJ, Gunzel P, Neumann F. Evaluation of effects of sexual steroids on the hypothalamic-pituitary system of animals and man. Arch Toxicol Suppl. 1979;2:11-39
58. Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von Zur Muhlen A. Circadian and pulsatile TSH secretion under physiological and pathological conditions. Horm Metab Res Suppl. 1990; 23:12-7
59. Re RN, Kourides IA, Ridgeway EC, Weintraub BD, Maloof F. The effect of glucocorticoid administation on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab. 1976; 43:338-46.
60. Atterwill CK, Catto LC, Heal DJ, Holland CW, Dickens TA, Jones CA. The effects of desipramine (DMI) and electroconvulsive shock (ECS) on the function of the hypothalamo-pituitary-thyroid axis in the rat. Psychoneuroendocrinology. 1989;14(5):339-46
61. Kaptein EM, Kletzsky OA, Spencer CA, NicoloffJT. Effects of prolonged dopamine infusion on anterior pituitary function in normal males. J Clin Endocrinol Metab 1980; 51:488-91
62. Samuels MH, Kramer P, Wilson D, Sexton F. Effect ofnaloxone infusions on pulsatile thyrotropin secretion. J Clin Endocrinol Metab. 1994;78(5):129-32.
63. Burger A, Nicod DP, Lemarchaud-Beraud T, Vallotton MB. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxine and thyrotropin. J Clin Invest 1976; 58: 255-9
64. Davis PJ, Davis FB, Utiger RD, Kulaga SF Jr. Changes in serum thyrotropin (TSH) in man during halofenate administration. J Clin Endocrinol Metab 1976; 43(4): 873-81
65. Trainer PI, Holly 1, Medbak S, Rais LH, Besser GM. The effect of recombinant IGF-1 on anterior pituitary function in healthy volunteers. Clin Endocrinol (Chef) 1994; 41(6): 801-7.

Toxic foods: MSG, alcohol

66. Bakke JL, Lawrence N, Bennett J, Robinson S, Bowers CY. Late endocrine effects of administering monosodium glutamate to neonatal rats. Neuroendocrinology 1978; 26(4): 220-8.
67. Greeley GH Jr, Nicholson GF, Kizer JS. A delayed LH/FSH rise after gonadectomy and a delayed serum TSH rise after thyroidectomy in monosodium-L-glutamate (MSG)-treated rats. Brain Res 1980; 195(1):111-22.
42. Modigliani E, Periac P, Perret G, Hugues JN, Coste T. TRH response in 53 patients with chronic alcoholism. Ann Med Interne Paris. 1979; 130(5): 297-302

Thyroid diseases: hyperthyroidism, Graves-Basedow disease, nodular goiter, thyroiditis, secondary or tertiary hypothyroidism, congenital hypothyroidism

68. Spencer CA, Lai-Rosenfeld AO, Guttler RB, LoPresti J, Marcus AO, Nimalasuriya A, Eigen A, Doss RC, Green BJ, Nicoloff JT. Thyrotropin secretion in thyrotoxic and thyroxine-treated patients: assessment by a sensitive immunoenzymometric assay. J Clin Endocrinol Metab. 1986 Aug;63(2):349-55
69. Yeo PP, Loh KC. Subclinical thyrotoxicosis. Adv Intern Med 1998; 43: 501-32
70. Chanson P. Insuffisance thyrotropic. Rev Prat. 1998 15; 48(18): 2023-6
71. Petersen PH, RosleffF, Rasmussen J, Hobolth N. Studies on the required analytical quality of TSH measurements in screening for congenital hypothyroidism. Scand J Clin Lab Invest Suppl. 1980;155: 5-93.
72. Fofanova 0V, Takamura N, Kinoshita E, Yoshimoto M, Tsuji Y, Peterkova VA, Evgrafov 0V, Dedov II, Goncharov NP, Yamashita S. Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. Am J Med Genet 1998; 77(5): 360-5.

FACTORS that ELEVATE the serum TSH

Neonatus, stress – emotional arousal, cold exposure, sleep deprivation, adrenal insufficiency, recovery from severe illness, congenital malformations

73. Hashimoto H, Sato F, Kubo M, Ohki T. Maturation of the pituitary-thyroid axis during the perinatal period. Endocrinol Jpn 1991;38(2):151-7
74. Gendrel D, Feinstein MC, Grenier J, Roger M, Ingrand J, Chaussain JL, Canlorbe P, Job JC. Falsely elevated serum thyrotropin (TSH) in newborn infants: Transfer from mothers to infants of a factor interfering in the TSH radioimmunoassay. J Clin Endocrinol Metab 1981;52(1):62-5.
75. Armario A, Lopez Calderon A, Jolin T, Castellanos JM. Sensitivity of anterior pituitary hormones to graded levels of psychological stress. Life Sci 1986; 39(5): 471-5
76. Reed HL, Silverman ED, Shakir KM, Dons R, Burman KD, O’Brian JT. Changes in serum triiodothyronine (TQ kinetics after prolonged Antarctic residence: The polar T3 syndrome. J Clin Endocrinol Metab. 1990; 70(4): 965-74
77. Sadamatsu M, Kato N, Iida H, Takahashi S, Sakaue K, Takahashi K, Hashida S, Ishikawa E. The 24-hour rhythms in plasma growth hormone, prolactin and thyroid stimulating hormone: effect of sleep deprivation. J Neuroendocrinol. 1995 Aug;7(8):597-606
78. Sjoberg S, Wemer S. Increased level of TSH can be a sign of adrenal cortex failures: Net necessarily of thyroid gland disease. Lakartidningen 1999; 96(5):464-5
79. De Nayer P, Dozin B, Vandeput Y, Bottazzo FC, Crabbe J. Altered interaction between triiodothyronine and its nuclear receptors in absence of cortisol: A proposed mechanism for increased thyrotropin secretion in corticoid deficiency states. Eur J Clin Invest. 1987 Apr;17(2):106-8
80. Oakley GA, Muir T, Ray M, Girdwood RW, Kennedy R, Donaldson MD. Increased incidence of congenital malformations in children with transient thyroid-stimulating hormonal elevation on neonatal screening. J Pediatr. 1998; 132(4): 573-4

Medications: iodine, antithyroidea, , lithium, neuroleptica (haloperidol, chlorpromazine), cimetidine, sulfapyridine, clomifen, antidepressants (sertraline), antihistaminic agents, cholestograhic agents, etc.

30. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8):591-9
81. Kleinmann RE, Vagenakis AG, Braverman LE. The effect of iopanoic acid on the regulation of thyrotropin secretion in euthyroid subjects. J Clin Endocrinol Metab. 1980;51(2): 399-403
82. Mc Caven KC, Garber JR, Spark R. Elevated serum thyrotropin in thyroxine-treated patients with hypothyroidism given sertraline. N Engl J Med. 1997; 337(14):1010-1
83. Brown CG, Harland RE, Major IR, Atterwill CK. Effects of toxic doses of a novel histamine (H2) antagonist on the rat thyroid gland. Food Chem Toxicol. 1987; 25(10):787-94

Auto-immune thyroiditis and hypothyroidism: primary, iodine-deficient, thyroid hormone resistance

30. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8): 591-9
84. Missler U, Gutekunst R, Wood WG. Thyroglobulin is a more sensitive indicator of iodine deficiency than thyrotropin: Development and evaluation of dry blood spot assays for thyrotropin and thyroglobulin in iodine- deficient geographical areas. Eur J Clin Chem Clin Biochem 1994; 32(3): 137-43
85. Volpe R. Subacute (de Quervain’s) thyroiditis. J Clin Endocrinol Metab. 1979 Mar;8(1):81-95
86. Massoudi MS, Meilahn EN, Orchard TJ, Foley TP Jr, Kuller LH, Costantino JP, Buhari AM. Thyroid function and perimenopausal lipid and weight changes: the Thyroid Study in Healthy Women (TSH-W). J Womens Health. 1997 Oct;6(5):553-8
87. Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG. Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies. Am J Med. 1989 Mar;86(3):289-96
TSH-secreting tumors (rare)
88. Smallridge RC. Thyrotropin-secreting pituitary tumors, Endocrinol Metab Clin North Am 1987 Sep;16(3):765-92

FACTORS that ELEVATE or DEPRESS serum TSH

Physiological serum TSH fluctuations

89. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9
90. Brabant G, Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von zur Muhlen A. Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res Suppl. 1990;23:12-7
91. Goichot B, Brandenberger G, Schlienger JL. Secretion of thyrotropin during states of wakefulness and sleep. Physiological data and clinical applications. Presse Med. 1996;25(21):980-4
92. Rao ML, Gross G, Strebel B, Halaris A, Huber G, Braunig P, Marler M. Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry. 1994;1:35(3): 151-63
93. Rose SR, Nisula BC. Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab. 1989; 68(6):1086-90
94. Scanlon MF, Weetman AP, Lewis M, Pourmand M, Rodriguez Arnao MD, Weightman DR, Hall R. Dopaminergic modulation of circadian thyrotropin rhythms and thyroid hormone levels in euthyroid subjects. J Clin Endocrinol Metab. 1980 Dec;51(6):1251-6
95. Rom Bugoslavskaia ES, Shcherbakova VS. Seasonal characteristics of the effect of melatonin on thyroid function. Bull Eksp Biol Med. 1986;101(3):268-9

Variations in the biological activity of TSH

96. Beck-Peccoz P, Persani L. Variable biological activity of thyroid stimulating hormone. Eur J Endocrinol. 1994 Oct;131(4):331-40
97. Maes M, Mommen K, Hendrickx D, Peeters D, D’Hondt P, Ranjan R, De Meyer F, Scharpe S. Components of biological variation of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin Endocrinol (Oxf). 1997 May;46(5):587-98
98. Hiromoto M, Nishikawa M, Ishihara T, Yoshikawa N, Yoshimura M, Inada M. Bioactivity of thyrotropin (TSH) in patients with central hypothyroidism: Comparison between the in vivo 3,5,3′- triiodo-thyronine response to TSH and in vitro bioactivity of TSH. J Clin Endocrinol Metab. 1995 Apr;80(4):1124-8

TSH test kit imperfections

99. Rasmussen AK, Hilsted L, Perrild H, Christiansen E, Siersbaek-Nielsen K, Feldt-Rasmussen U. Discrepancies between thyrotropin (TSH) meaasurement by four sensitive immunometric assays. Clin Chim Acta. 1997 Mar 18;259(1-2):117-28
100. Libeer JC, Simonet L, Gillet R. Analytical evaluation of twenty assays for determination of thyrotropin (TSH). Ann Biol Clin Paris. 1989; 47(1): 1-11
101. Spencer CA, Takeuchi M, Kazarosyan M, MacKenzie F, Beckett GJ, Wilkinson E. Interlaboratory/intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentrations of TSH. Clin Chem. 1995 Mar;41(3):367-74
102. Faber J, Gam A, Siersbaek Nielsen K. Improved sensitivity of serum thyrotropin measurements: Studies on serum sex hormone-binding globulin in patients with reduced serum thyrotropin. Acta Endocrinol Copenh 1990; 123(5): 535-40
103. Laurberg P. Persistent problems with the specificity of immunometric TSH assays. Thyroid. 1993 Winter;3(4):279-83
104. Schlienger JL, Sapin R, Grunenberger F, Gasser F, Pradignac A. Thyrotropin assay by chemiluminescence in the diagnosis of dysthyroidism with low thyrotropin and normal thyroid hormones levels. Pathol Biol Paris. 1993; 41(5): 463-8
105. Spencer C, Eigen A, Shen D, Duda M, Qualls S, Weiss S, Nicoloff J. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987 Aug;33(8):1391-6
106. Spencer CA, Challand GS. Interference in a radioimmunoassay for human thyrotropin. Clin Chem 1977;23(3): 584-8
107. Kahn BB, Weintraub BD, Csako G, Zweig MH. Factitious elevation of thyrotropin in a new ultra-sensitive assay: Implications for the use of monoclonal antibodies in ‘sandwich’ immuno-assay. J Clin Endocrinol Metab. 1988 Mar;66(3):526-33
108. Kourides IA, Weintraub BD, Martorana MAL, Maloof F. Alpha subunit contamination of human albumin preparations: Interference in radioimmunoassay. J Clin Endocrinol Metab. 1976; 43(4): 919-23
109. Bartlett WA, Browning MC, Jung RT. Artefactual increase in serum thyrotropin concentration caused by heterophilic antibodies with specificity for IgG of the family Bouidea. Clin Chem. 1986; 32(12): 22(4-9)
110. Csako G, Weintraub BD, Zweig MH. The potency of immunoglobulin antibodies in a monoclonal immunoradiometric assay for thyrotropin. Clin Chem. 1988 Jul;34(7):1481-3
111. Seghers J, Schruers F, De Nayer P, Beckers C. Interference in thyrotropin (TSH) determination: Falsely elevated TSH values in a transplanted patient. Eur J Nucl Med. 1989; 15(4): 194-6
112. Spencer C, Eigen A, Shen D, Duda M, Quails S, Weiss S, Nicoloff J. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987;33(8):1391-6
113. Ealey PA, Marshall NJ, Ekins RP. Time-related thyroid stimulation by thyrotropin and thyroid-stimulating antibodies, as measured by the cytochemical section bioassay. J Clin Endocrinol Metab. 1981;52(3): 483-7

Beware for overreliance on thyroid laboratory tests

115. Rippere V. Biochemical victims: False negative diagnosis through overreliance on laboratory results—a personal report. Med Hypotheses. 1983; 10(2): 113.

Other tests : urinary T3 as a complementary test

116. Baisier W, Hertoghe J, Eeckhaut W. Thyroid insufficiency Is TSH measurement the only diagnostic tool? J Nutr Environm Med. 2000; 10(3): 109-113.

THYROID TREATMENT DISCUSSIONS:

Does thyroid treatment definitely suppress thyroid gland?

No, after stopping thyroid medications, the thyroid axis recovers its initial condition generally in 2 to 3 weeks

Krugman LG, Hershman JM, Chopra IJ, Levine GA, Pekary E, Geffner DL, Chua Teco GN. Patterns off recovery of the hypothalamic-pituitary-thyroid axis in patients taken of chronic thyroid therapy. J Clin Endocrinol Metab. 1975 Jul;41(1):70-80 (full recoveryback to initial serum T3, T4, TSH levels is obtained after a mean of 16 to 22 days, even after 28 years of treatment)

Vagenakis AG, Braverman LE, Azizi F, Portinay GI, Ingbar SH. Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med. 1975 Oct 2;293(14):681-4 (“During exogenous hormone administration, 131l uptake was suppressed, and serum thyrotropin concentrations before and after administration of thyrotropin-releasing hormone were undetectable. …. After withdrawal of long-term thyroid hormone, decreased thyrotropin reserve persisted for two to five weeks. Detectable values of serum thyrotropin (less than 1.2 muU per milliliter) and a normal 131l uptake usually occurred concurrently in two to three weeks. Serum thyroxine concentration returned to normal at least four weeks after hormone withdrawal.”)

Greer MA. The effect on endogenous thyroid activity of feeding desiccated thyroid to normal human subjects. N Engl J Med. 1951 Mar 15;244(11):385-90 (“After withdrawal of thyroid therapy, thyroid function returned to normal in most subjects within 2 weeks, although a few were depressed ofr 6-11 weeks. Thyroid function returned as rapidly in those whose glands had been depressed by several years of thyroid medication as it did for those whose glands had been depressed for only a few days.”)

Mosier HD, DeGolia RC. Effect of prolonged administration of thyroid hormone on thyroid gland function of euthyroid children. J Clin Endocrinol Metab. 1960 Sep;20:1296-301. (“In all of the echildren and adolescents included in this study, thyroid function returned to normal (as judged by clinical signs ans by laboratory measurements) within four months after discontinuing thyroid hormone,in spite of previous administration of suppressive doses for periods of 20 too 125 months during years of somatic growth”).

Farquharson RF, Squires AH. Inhibition of the secretion of the thyroid gland by continued ingestion of thyroid substance. Tr A Am Physicians. 1941;56:87

Johnston MW, Squires AH, Farquharson RF. The effect of prolonged administration of thyroid. Ann Intern Med. 1951 Nov;35(5):1008-22

Riggs DS, Man EB, Winkler AW. Serum iodine of euthyroid subjects treated with dessicated thyroid. J Clin Invest. 1945;24:722-31

Stein RB, Nicoloff JT. Triiodothyronine withdrawal test -a test of thyroid-pituitary adequacy. J Clin Endocrinol Metab. 1971 Feb;32(2):127-9

If the thyroid treatment is stopped because it is judged not necessary, recovery takes place

Rubinoff H, Fireman BH. Testing for recovery of thyroid function after withdrawal of long-term suppression therapy. J Clin Epidemiol. 1989;42(5):417-20 (At 8 weeks, 30 of the 45 patients whose chart reviews did not demonstrate a clear need for thyroid replacement., were normal)
Department of Medicine, Kaiser Permanente Medical Center, Oakland, CA 94611.

Mild thyroid failure: to treat or not to treat

Arguments PRO THYROID USE for mild thyroid failure

Studies that show the efficacy of treating mild thyroid failure

Little benefit of T4 therapy if TSH reductions are put into only the range of 3–3.5 mU/lL. Mainly studies using dosage titration to TSH levels < 3.0 are associated with improvement in symptoms, lipid abnormalities, and cardiovascular function (except the study by Meier and colleagues that showed benefit with minimal TSH reductions in the 3-3.5 mIU/ml range)

21. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism. Am J Med. 2001;112:348–54
22. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001; 86:4860–6
Cooper DS 2001 Subclinical hypothyroidism. N Engl J Med 345:260–5
Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44–50
20. McDermott MT, Ridgway EC. Clinical perspective: subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001; 86:4585–90 (shows benefit with minimal TSH reductions down to only the range of 3–3.5 mU/liter)

Studies with appropriate dosage titration to TSH levels under 3.0 are more often associated with improvement in symptoms, lipid abnormalities, and cardiovascular function

1. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism. Eur J Endocrinol. 1998;138:141–5
Ayala A, Wartofsky L 2002 The case for more aggressive screening and treatment of mild thyroid failure (“subclinical” hypothyroidism). Cleveland Clin J Med 69:313–20
37. Faber J, Petersen L, Wiinberg N, Schifter S, Mehisen J. Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid. 2002; 12:319–24
38. Monzani F, DiBello V, Caraccio N, Bertini A, Giorgi D, Guisti C, Ferranni E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001; 86:1110–5
39. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999; 84:2064–7
40. Di Bello V, Monzani F, Giorgi D, Bertini A, Caraccio N, Valenti G, Talini E, Paterni M, Ferrannini E, Giusti C. Ultrasonic myocardial textural analysis in subclinical hypothyroidism. J Am Soc Echocardiogr. 2000;13:832–40
41. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stametelopoulos S, Koutras DA. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin values. Thyroid. 1997; 7:411-4
42. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731–7
43. Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 86:1206–11
44. Krausz Y, Freedman N, Lester H, Newman JP, Barkai G, Bocher M, Chisin R, Bonne O. Regional cerebral blood flow in patients with mild hypothyroidism. J Nucl Med. 2004; 45:1712–5
45. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokayama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004;89:3365–70
46. Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, Taddei S, Palombo C, Ferrannini C. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89:2099–106

Other studies in defence of treatment of mild thyroid failure: it is mportant to treat mild thyroid failure to avoid adverse physical and psychological consequences

19. Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993 May;71(5):367-71
Tappy L, Randin JP, Schwed P, Wertheimer J, Lemarchand-Beraud T. Prevalence of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not dementia. J Am Geriatr Soc. 1987;35:526–31
20. Joffe RT, Levitt AJ 1992 Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 17:215–21
21. Haggerty Jr JJ, Stern RA, Mason GA, Beckwith J, Morey CE, Prange Jr AJ. Subclinical hypothyroidism: A modifiable risk factor for depression? Am J Psychiatry. 1993;150:508–10
22. Manciet G, Dartigues JF, Decamps A, et al. 1995 The PAQUID survey and correlates of subclinical hypothyroidism in elderly community residents in the southwest of France. Age Aging. 24:235-41
Baldini IM, Vita A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35
23. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry. 1996;40:714–25
24. Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini E. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab. 1997;82:3315–8
25. Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy. Clin Endocrinol. 1999;51:237–42
26. Misiunas A, Ravera HN, Faraj G, Faure E. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995;5:283–6
Goulis DG, Tsimpiris N, Delaroudis S, Maltas B, Tzoiti M, Dagilas A, Avramides A. Stapedial reflex: a biological index found to be abnormal in clinical and subclinical hypothyroidism. Thyroid. 1998 Jul;8(7):583-7
Beyer IW, Karmali R, DeMeester-Mirkine N, Cogan E, Fuss MJ. Serum creatine kinase levels in overt and subclinical hypothyroidism. Thyroid 1998;8:1029–31
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549-55
Foundation for Blood Research, Scarborough, ME 04074, USA
Ridgway EC, Cooper DS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1981 Dec;53(6):1238-42
27. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med. 1984;101:18–24
28. Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg P-A, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ’subclinical’ hypothyroidism. Clin Endocrinol. 1988;29:63–76 (Approximately one woman in four with this ‘subclinical’ condition will benefit from L-thyroxine treatment)
29. Bell GM, Todd WT, Forfar JC, Martyn C, Wathen CG, Gow S, Riemersma R, Toft AD. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1985 Jan;22(1):83-9
Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL, Toft AD. Left ventricular performance in subclinical hypothyroidism. Q J Med. 1985 Dec;57(224):857-65 Foldes J, Istvanfy M, Halmagyi M, Varadi A, Gara A, Partos O. Hypothyroidism and the heart. Examination of left ventricular function in subclinical hypothyroidism. Acta Med Hung. 1987;44:337–47
30. Kahaly GJ 2000 Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 10:665–79
31. Arem R, Rokey R, Kiefe C, Escalante DA, Rodriquez A. Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: Effect of thyroid hormone therapy. Thyroid. 1996 ;6:397-402
32. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001 Mar;86(3):1110-5
Department of Internal Medicine, University of Pisa School of Medicine, 56126 Pisa, Italy. [email protected]
33. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999 Jun;84(6):2064-7
Department of Endocrinology of the University Federico II, Naples, Italy.
33. Tanis BC, Westendorp RGJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol. 1996;44:643–9
34. Danese MD, Ladenson PW, Meinert CL, Powe NR; Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85:2993–3001
35. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5
36. Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol. 1999;50:217–20
37. Bakker SJL, Ter Matten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001;86:1206–11
38. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid. 1997;7:411–4
39. Powell J, Zadeh JA, Carter G, Greenhalgh RM, Fowler PB. Raised serum thyrotrophin in women with peripheral arterial disease. Br J Surg. 1987;74:1139–41
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Rodgers H, Tunbridge F, Young ET. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 1996 Jun;6(3):155-60
Department of Medicine, Newcastle General Hospital, Newcastle upon Tyne, United
Kingdom.
40. Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996 Dec;11(12):744-9
40. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995;155:1490–5
41. Perk M, O’Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997;13:273–6
42. Stockigt J. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid. 2000, ed 8. Philadelphia: Lippencott Williams and Wilkins; 376–92
43. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA. 1996;276:285–92
44. McDermott MT, Haugen BR, Lezotte DC, Seggelke S, Ridgway EC. Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients. Thyroid. 2001;11:757–76
Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33 (impairment of systolic ejection, a delay in diastolic relaxationand a decrease in the compliance to the ventricular filling. Several significant correlations were found between the parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis)

Subclinical thyroid dysfunction is an abnormal serum thyroid-stimulating hormone level (reference range: 0.45 to 4.50 µU/mL) and free thyroxine and triiodothyronine levels within their reference ranges

Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24 Department of Community Health and Family Medicine, University of Florida Health Science Center, Jacksonville, Florida 32209, USA. [email protected]

Important frequency of subclinical hypothyroidism:

1. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG,
Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977 Dec;7(6):481-93
2. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
3. Hollowell J, Braverman LE, Spencer CA, Staehling N, Flanders D, Hannon H Serum TSH, T4, and thyroid antibodies in the United States population: NHANES III. 72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL, 1999; Abstract 213
4. Guel KW, van Sluisveld IL, Grobbee DE, Docter R, de Bruyn AM, Hooykaas H, van der Merwe JP, van Hemert AM, Krenning EP, Hennemann G, et al. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf). 1993 Sep;39(3):275-80
5. Rivolta G, Cerutti R, Colombo R, Miano G, Dionisio P, Grossi E. Prevalence of subclinical hypothyroidism in a population living in the Milan metropolitan area. J Endocrinol. Invest. 1999;22:693–7
6. Bagchi N, Brown TR, Parish RF. Thyroid dysfunction in adults over age 55 years. A study in an urban U.S. community. Arch Intern Med. 1990;150:785–7
7. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA. 1979;242:247–50
8. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, Koehler KM, Garry PJ. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc. 1999 Jun;47(6):703-9
9. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam study. Ann Intern Med. 2000;132:270–8
10. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA. 1987 ;258:209–13
Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24 (The prevalence of subclinical hypothyroidism is about 4 to 8.5 percent, and may be as high as 20 percent in women older than 60 years)
Department of Community Health and Family Medicine, University of Florida Health Science Center, Jacksonville, Florida 32209, USA. [email protected]

Important risk of progression into overt hypothyrodism:

11. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77–83
12. Bastenie PA, Bonnyns M, Vanhaelst L. Natural history of primary myxedema. Am J Med. 1985;79:91–100
13. Kabadi UM. Subclinical hypothyroidism. Natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957–61
Tunbridge WMG, Brewis M, French JM, Appleton D, Bird T, Clark F, Evered DC, Evans JG, Hall R, Smith P, Stephenson J, Young E. Natural history of autoimmune thyroiditis. Br Med J (Clin Res Ed). 1981 Jan 24;282(6260):258-62
14. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F,Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68
15. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am. 1997;26:189–218
16. Huber G, Mitrache C, Guglielmetti M, Huber P, Staub JJ. Predictors of overt hypothyroidism and natural course: a long-term follow-up study in impending thyroid failure. 71st Annual Meeting of the American Thyroid Association, Portland, OR, 1998; Abstract 109

Importance of clinical evaluation of subclinical hypothyroidism

Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771–6

Studies showing that for other diseases such as diabetes and hypertension, it is important to treat mild glandular failure

54. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1C with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med. 2004;141:413–20
55. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004 351:33–41
56. Dluhy RG, Williams GH. Aldosterone: villain or bystander? N Engl J Med. 2004;351:8–10

Arguments CONTRA THYROID USE for mild thyroid failure

22. Chu JW, Crapo LM. Should mild hypothyroidism be treated? Am J Med. 2002;112:422–3
23. Chu JW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab. 2001;86:4591–9

Initiation of levothyroxine therapy for mild thyroid failure would be inappropriate because it results in overtreatment with attendant risks of subclinical hyperthyroidism.
(Critic: this risk applies to a very small fraction of the population to be treated. An equivalent risk of undertreatment of such individuals applies as well. Both results could be minimized by education of our primary care physicians about the desirable TSH target in their patients)

1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228–38
3. Surks MI. Commentary: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586–7

T4 in clinically hypothyroid patients but normal tests: does not improve

Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, McLaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001 Oct 20;323(7318):891-5

T4 treatment in subclinically hypothyroid patients but normal tests: does not improve the patient (explanation: The absence of clinically relevant benefits of thyroid therapy for mild thyroid failure may be due to (1) aTSH normalization that was typically described as lowering of TSH to < 5 mU/liter, whereas levels between 3 – 5 mU are probably still elevated and request higher dosage; (2) the use of thyroxine without any addition of triiodothyronine)

19. Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, Dore CJ, Finer N. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002;112:348–54

Thyroxine treatment does improve cholesterol levels and clinical symptoms in subclinical hypothyroidism

20. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001 Oct;86:4860–6 (An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in LDL cholesterol)

Studies that show the importance of treating mild thyroid excess

Subclinical hyperthyroidism: There is an equal concern about appropriate diagnosis and treatment of patients with TSH levels that are slightly below the reference interval because of risks to both heart and bone

21. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5
52. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D’Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249–52
53. Stathatos N, Wartofsky L. Effects of thyroid hormone on bone. Clin Rev Bone Miner Metab. 2004;2:135–50

Controversy on the best thyroid treatment: T4 or T4-T3?

PRO T4 alone:

Guidelines on T4 recommendation

Brent GA, Larsen PR. Treatment of hypothyroidism. In: Braverman LE, Utiger RD, ed. Werner and Ingbar’s. The Thyroid: A Fundamental and Clinical Text. 7th ed., 1996, Philadelphia, Ravens- Lippincott Publishers
Utiger RD. Hypothyroidism. In DeGroot LJ et al, eds. Endocrinology, Vol 1. 2nd ed. Philadelphia, Pa: WB Saunders Co, 1989;702-21
Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993;119:492-502
Roti E, Braverman LE. Thyroid hormone therapy: when to use it, when to avoid it. Drug Therapy. 1994; 24(4):2-35.

T4 and T3- work as good as T4 alone, but not better

Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005 Jul-Aug;11(4):223-33
Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003 Oct;88(10):4551-5

T3-T4 (and T3) work better than T4

Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. Clin Endocrinol Metab. 2005 Feb;90(2):805-12
1032. Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on musculoskeletal symptoms. Clin Rheumatol. 1993 Sep;12(3):341-5
45. Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine, Ed. German Society of Anti-Aging Medicine-Verlag 2003- 2004; 32-43
76. Pareira VG, Haron ES, Lima-Neto N, Medeiros-Neto GA. Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. J Endocrinol Invest. 1982;5:331-4
77. Chernow B, Burman KD, Johnson DL, McGuire RA, O’Brian JT, Wartofsky L, Georges LP. T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. Crit Care Med. 1983 Feb;11(2):99-104
78. Arlot S, Debussche X, Lalau JD, Mesmacque A, Tolani M, Quichaud J, Fournier A. Myxoedema coma: response of thyroid hormones with oral and intravenous high-dose L-thyroxine treatment. Intensive Care Med. 1991;17(1):16-8
Service de Medecine Interne-Endocrinologie, Centre Hospitalier Regional, France

T3-T4 treatment: adding T3 to T4 results in more improvement of clinical symptoms and signs of hypothyroidism in patients

Benevicius R, Kazanavicius G, Zalinkovicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med.1999; 340: 424-9.

When T3 and T4 are both supplemented to the food simultaneously with goitrogens, a much better prevention of goiter is obtained than when solely T4 at even 7 times higher concentration is added

Devlin WF, Watanabe H. Thyroxin-triiodothyronine concentrations in thryoid powders. J Pharm Sci. 1966 Apr;55(4):390-3

In humans, T4-T3 treatments reduce serum cholesterol and increase the speed of the Achilles tendon reflexes more than T4 treatments alone

Alley RA, Danowski TS, Robbins T JL, Weir TF, Sabeh G, and Moses CL. Indices during administration of T4 and T3 to euthyroid adults. Metabolism. 1968;17(2):97-104

A study in rats rendered hypothyroid shows that cellular euthyroidism is only obtained in the target organs of hypothyroid rats if T3 is added to the classic T4 medication

Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996 Jun;137(6):2490-502
Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995 Dec;96(6):2828-38

Medications with T4 alone do not succeed in achieving complete cellular euthyroidism in the target organs, probably because T3 is really the active hormone

Asper SP Jr, Selenkow HA, and Plamondon CA. A comparaison of the metabolic activities of 3,5,3’-triiodothyronine and l-thyroxine in myxedema. Bull John Hopkins Hosp. 1953; 93: 164
Blackburn CM, McConahey WM, Keating FR Jr, Albert A. Calorigenic effects of single intravenous doses of l-triiodothyronine and l-thyroxine in myxedematous persons. J Clin Invest. 1954 Jun;33(6):819-24

T3 is much more potent than T4

Gross J, Pitt-Rivers R. Physiological activity of 3:5:3′-L-triiodothyronine. Lancet. 1952 Mar 22;1(12):593-4
Gross J, Pitt-Rivers R. 3:5:3′-triiodothyronine. 2. Physiological activity. Biochem J. 1953 Mar;53(4):652-7

Conditions that reduce the conversion of T4 to T3 such as aging, obesity, disease, stress, exercise, malnutrition, etc.

Burroughs V, Shenkman L. Thyroid function in the elderly. Am J Med Sci. 1982, 283 (1): 8-17
Carter JN, Eastman CJ, Corcoran JM, and Lazarus L. Inhibition of conversion of thyroxine to triiodothyronine in patients with severe chronic illness. Clin Endocrinol. 1976; 5: 587-94
Tulp OL and McKee TD Sr. Triiodothyronine neogenesis in lean and obese LA/N-cp rats. Biochem Biophys Res Communications. 1986; 140 (1): 134-42
Katzeff HI, Selgrad C. Impaired peripheral thyroid hormone metabolism in genetic obesity. Endocrinology. 1993; 132 (3): 989-95
Croxson MS and Ibbertson HK. Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endocrinol Metab. 1977; 44: 167-73
Harns ARC, Fang SH, Vagenakis AG, and Braverman LE. Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat. Metabolism. 1978;27(11):1680-90
Opstad PK, Falch D, Öktedalen O, Fonnum F, and Wergeland R. The thyroid function in young men during prolonged physical exercise and the effect of energy and sleep deprivation. Clin Endocrinol. 1984; 20: 657-69
Walfish PG. Triiodothyronine and thyroxine interrelationships in health and disease. Can Med Ass. J 1976, 115: 338-42

Toxic substances such as phenols, cadmium, mercury, etc, and medications such as propranolol, amiodarone and several others may interfere by stimulating or inhibiting the T4 to T3 conversion

Feyes D, Hennemann G and Visser TJ. Inhibition of iodothyronine deiodinase by phenolphtalein dyes. Fed Eur Biomed Sci. 1982; 137(1):40-4
Bahn AK, Mills JL, Snyder PJ, Gann PH, Houten L, Bialik O, Hollmann L, and Utiger RD. Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med. 1980; 302: 31-3
Ikeda T, Ito Y, Murakami I, Mokuda O, Tominaga M and Mashiba H. Conversion of T4 to T3 in perfused liver of rats with carbontetrachloride-induced liver injury. Acta Endocrinol. 1986;112: 89-92
Paier B, Hagmüller K, Nolli Mi, Gonzalez Pondal M, Stiegler C and Zaninovich AA. Changes induced by cadmium administration on thyroxine deiodination and sulfhydryl groups in rat liver. J Endocrinol. 1993; 138: 219-24
Barregärd L, Lindstedt G, Schütz A, Sällsten G. Endocrine function in mercury exposed chloralkali workers. Occup Envir Med. 1994; 51: 536-40

Deficiencies in hormones (T3 itself, TSH, growth hormone, insulin, melatonin, etc) and trace elements (selenium, iron, zinc, cupper, etc) partially block this essential step for thyroid function

Burger AG, Lambert M, Cullen M. Interférence de substances médicamenteuses dans la conversion de T4 en T3 et rT3 chez l’homme. Ann Endocrinol (Paris). 1981,42:461-9
Grussendorf M, Hüfner M. Induction of the thyroxine to triiodothyronine converting enzyme in rat liver by thyroid hormones and analogs. Clin Chim Acta. 1977;80:61-6
Erickson VJ, Cavalieri RR, Rosenberg LL. Thyroxine-5’-diodinase of rat thyroid, but not that of liver, is dependent on thyrotropin. Endocrinology. 1982;111:434-40
Rezvani I, DiGeorge AM, Dowshen SA, Bourdony CJ. Action of human growth hormone on extrathyroidal conversion of thyroxine to triiodothyronine in children with hypopituitarism. Pediatr Res. 1981;15:6-9
Schröder-Van der elst JP, Van der heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes. 1992;41:147-52
Gavin LA, Mahon FA, Moeller M. The mechanism of impaired T3 production from T4 in diabetes. Diabetes. 1981;30:694-9
Hoover PA, Vaughan MK, Little JC, Reiter RJ. N-methyl-D-aspartate does not prevent effects of melatonin on the reproductive and thyroid axes of male Syrian hamsters. J Endocrinology. 1992;133:51-8
Chanoine J-P, Safran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord S, Alex s, Arthur JR, Beckett GJ, Braverman LE, Leonard JL. Selenium deficiency and type II 5’-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine. Endocrinology. 1992;130:479-84
Arthur JR, Nicol F, Beckett GJ. Selenium deficiency, thyroid hormone metabolism, and thyroid hormone deiodinases. Am J Clin Nutr Suppl. 1993; 57:236S-9S
Beard J, Tobin B, and Green W. Evidence for thyroid hormone deficiency in iron-deficient anemic rats. J Nutr. 1989;772-8
Fujimoto S, Indo Y, Higashi A, Matsuda I, Kashiwabara N, and Nakashima I. Conversion of thyroxine into triiodothyronine in zinc deficient rat liver. J Pediatr Gastroenterol Nutr. 1986;5:799-805
Olin KI, Walter RM, and Keen CL. Copper deficiency affects selenoglutathione peroxidase and selenodeiodinase activities and antioxidant defense in weanling rats. Am J Clin Nutr 1994;59:654-8
Westgren U, Ahren B, Burger A, Ingemansson S, Melander A. Effects of dexamethasone, desoxycorticosterone, and ACTH on serum concentrations ot thyroxine, 3,5,3’-triiodothyronine and 3,3’,5’-triiodothyronine. Acta Med Scand. 1977;202 (1-2): 89-92
On the other hand, excesses in hormones (glucocorticoids36,37, ACTH36, estrogens37,…) and trace elements (iodine38, lithium39, …) may slow down this conversion.
Heyma P, Larkins RG. Glucocorticoids decrease the conversion of thyroxine into 3,5,3’-triiodothyronine by isolated rat renal tubules. Clin Science. 1982; 62: 215-20
Scammell JG, Shiverick KT, Fregly MJ. Effect of chronic treatment with estrogen and thyroxine, alone and combined, on the rate of deiodination of l-thyroxine to 3,5,3’-triiodothyronine in vitro. Pharmacology. 1986;33: 52-7
Aizawa T, Yamada T. Effects of thyroid hormones, antithyroid drugs and iodide on in vitro conversion of thyroxine to triiodothyronine. Clin Exp Pharmacol Physiol. 1981; 8: 215-25
Voss C, Schrober HC, Hartmann N. Einfluss von Lithium auf die in vitro-Deioderung von l-Thyroxin in der Ratten leber. Acta Biol Med Germ. 1977; 36:1061-5
The absorption of oral T4 can be variable (50 to 73%40,41), contrasting with that of T3 that is more constant and efficient (95%)
Hays MT. Absorption of oral thyroxine in man. J Clin Endocrinol Metab. 1968; 28 (6):749-56
Surks MI, Schodlow AR, Stock Jm, Oppenheimer JH. Determination of iodothyronine absorption and conversion of L-thyroxine using turnover rate techniques. J Clin Invest. 1973; 52:809-11
Hays MT. Absorption of triidothyronine in man. J Clin Endocrinol Metab. 1970; 30(5):675-6

Defects in the commercial T4 preparation 43,44

Hubbard WK. FDA notice regarding levothyroxine sodium. Federal register. 1997; 62(157): 1-10
Peran S, Garriga MJ, Morreale de Escobar G, Asuncion M, Peran M. Increase in plasma thyrotropin levels in hypothyroid patients during treatment due to a defect in the commercial preparation . J Clin Endocrinol Metab. 1997;82(10):3192-5

Thyroid and the Heart

Claim: Thyroid hormone treatment is dangerous for the heart as it can cause side effects such as atrial fibrillation.
Facts: Euthyroidism (normal thyroid function) is essential for the heart; both hypothyroidism as well as hyperthyroidism impair the working of the heart and may facilitate atrial fibrillation.

CONTRA thyroid use:

Hyperthyroidism: causes tachycardia (critic: tachycardia is the result of hyperthyroidism, hypocorticism, or drinking of caffeinated beverages; avoiding these conditions by adequate treatment or abstention will generally prevent tachycardia)

Maciel BC, Gallo L Jr, Marin Neto JA, Maciel LM, Alves ML, Paccola GM, Iazigi N. The role of the autonomic nervous system in the resting tachycardia of human hyperthyroidism. Clin Sci (Lond). 1987 Feb;72(2):239-44
Abadie E, Leclercq JF, Fisch A, Babalis D, Blanche PM, Passa P, Coumel P. Pathogenesis of tachycardia in hyperthyroidism. Value of Holter monitoring and the use of a beta-blocker. Presse Med. 1985 Feb 2;14(4):197-9

Hyperthyroidism (high serum thyroid hormones) is associated with an increased risk of atrial fibrillation

Parmar MS. Thyrotoxic atrial fibrillation. Med Gen Med. 2005 Jan 4;7(1):74 (atrial fibrillation was seen in 15 % of hyperthyroid patients)
Northern Ontario School of Medicine, Laurentian University, Sudbury, Canada
Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216 (5.2 times more risk of atrial fibrillation in hyperthyroidism)
Department of Internal Medicine B, Ernst-Moritz-Arndt-University, Greifswald, Germany
Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med. 2004 Aug 9-23;164(15):1675 (atrial fibrillation was observed in 8.3 % of hyperthyroid patients)
Arhus Universitetshospital, Arhus Sygehus, Medicinsk-kardiologisk Afdeling A. [email protected]

Hyperthyroidism is associated with an increased risk of angina pectoris

Gitlin MJ. L-triiodothyronine-precipitated angina and clinical response. Biol Psychiatry. 1986 May;21(5-6):543-5

Possibility to give a betablocker together with thyroid medication to hypothyroid patients with angina pectoris

Ellyin F, Fuh CY, Singh SP, Kumar Y. Hypothyroidism with angina pectoris. A clinical dilemma. Postgrad Med. 1986 May 15;79(7):93-8

A high serum free & total T3 in patients aged 40years or older at emergency admission: increased risk of of angina pectoris and mycocardial infarct at admission & 3 yrs later (critic: possibly due to hypocorticism??)

Peters A, Ehlers M, Blank B, Exler D, Falk C, Kohlmann T, Fruehwald-Schultes B, Wellhoener P, Kerner W, Fehm HL. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med. 2000 Jul 10;160(13):1993-9

A high serum T4 can be found in patients with coronary heart disease (critic:probably with at the same time a low serum T3, which reflects a clinical more hypothyroid state, because of the decrease in conversion of T4 to T3 that is generally observed in the disease state)

Sidorenko BA, Begliarov MI, Titov VN, Masenko VP, Parkhimovich RM. Blood thyroid hormones in ischemic heart disease (a comparison with coronary angiographic data, severity of stenocardia and blood lipid level)] Kardiologiia. 1981 Dec;21(12):96-101
Selivonenko VG, Zaika IV. The function of the thyroid and thyrotropic function in patients with chronic ischemic heart disease and rhythm disorders. Lik Sprava. 1998 Jan-Feb;(1):81-3

PRO thyroid use: the heart needs to have thyroid hormones or heart disease appears

Thyroid hormone levels:

Thyroid hormone levels are positively correlated with the heart rhythm

Tseng KH, Walfish PG, Persaud JA, Gilbert BW. Concurrent aortic and mitral valve echocardiography permits measurement of systolic time intervals as an index of peripheral tissue thyroid functional status. J Clin Endocrinol Metab. 1989 Sep;69(3):633-8

Lower serum T3 (and higher serum T4) is found in heart patients with arrhythmia

Selivonenko VG, Zaika IV. The function of the thyroid and thyrotropic function in patients with chronic ischemic heart disease and rhythm disorders. Lik Sprava. 1998 Jan-Feb;(1):81-3
Inama G, Furlanello F, Fiorentini F, Braito G, Vergara G, Casana P. Arrhythmogenic implications of non-iatrogenic thyroid dysfunction. G Ital Cardiol. 1989 Apr;19(4):303-10 (Hypothyroidism in patients with hyperkinetic ventricular arrhythmias (25%), atrial fibrillation (37.5%) and atrio-ventricular block (37.5%))
Ospedale S. Chiara, Trento
Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Thyroid function in patients with ventricular arrhythmia. Kardiologiia. 1989 Feb;29(2):64-7 (Hyperthyroidism was diagnosed in 4.8% of 21 patients with persistent ventricular arrhythmias, and latent hypothyroidism was diagnosed in 38.1%)
Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Study of thyroid function in patients with paroxysmal supraventricular tachycardia. Kardiologiia. 1989 Jan;29(1):71-4
Nesher G, Zion MM. Recurrent ventricular tachycardia in hypothyroidism–report of a case and review
of the literature. Cardiology. 1988;75(4):301-6
Shaare Zedek Medical Center, Jerusalem, Israel
Fredlund BO, Olsson SB. Long QT interval and ventricular tachycardia of “torsade de pointe” type in
hypothyroidism. Acta Med Scand. 1983;213(3):231-5

Low serum T3 and T4 in patients with coronary heart disease

Miura S, Iitaka M, Suzuki S, Fukasawa N, Kitahama S, Kawakami Y, Sakatsume Y, Yamanaka K, Kawasaki S, Kinoshita S, Katayama S, Shibosawa T, Ishii J. Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endocr J. 1996 Dec;43(6):657-63

Low serum free T3 in patients with coronary bypass: increased risk of postoperative atrial fibrillation (higher risk than that of not taking a beta-blocker)

Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-92

Progressively lower serum T3 in patients with ischemic heart disease: form coronary stenosis to mycocardial infarct

Telkova IL, Tepliakov AT. Changes of thyroid hormone levels in the progression of coronary artery disease. Arteriosclerosis. Klin Med (Mosk). 2004;82(4):29-34
Pavlou HN, Kliridis PA, Panagiotopoulos AA, Goritsas CP, Vassilakos PJ. Euthyroid sick syndrome in acute ischemic syndromes. Angiology. 2002 Nov-Dec;53(6):699-707
Pimenov LT, Leshchinskii LA. Thyroid hormone changes (iodothyroninemia) in patients with acute myocardial infarction, and their clinical significance. Kardiologiia. 1984 Oct;24(10):74-7

Low serum free and total T3 (and low free T4 and high TSH) in patients suffering from acute mycocardial infarct with poor outcome

Satar S, Seydaoglu G, Avci A, Sebe A, Karcioglu O, Topal M. Prognostic value of thyroid hormone levels in acute myocardial infarction: just an epiphenomenon? Am Heart Hosp J. 2005 Fall;3(4):227-33

Auto-immune throidiits is associated with poorer heart indices

Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33 (impairment of systolic ejection, a delay in diastolic relaxationand a decrease in the compliance to the ventricular filling. Several significant correlations were found between the parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis)
Department of Cardiovascular Sciences, University of Cagliari, Sardinia, Italy

Increased incidence of auto-immune thyroiditis and overt hypothyroidism in men with acute mycocardial infarct, which may have contributed to the development of the disease.

Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003 Oct;24(4):487-92

A low serum T3 or T4 (hypothyroidism) is found in cardiac failure:

Khaleeli AA, Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinical, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473-6
Reza MJ, Abbasi AS. Congestive cardiomyopathy in hypothyroidism. West J Med. 1975 Sep;123(3):228-30
Rays J, Wajngarten M, Gebara OC, Nussbacher A, Telles RM, Pierri H, Rosano G, Serro-Azul JB. Long-term prognostic value of triiodothyronine concentration in elderly patients with heart failure. Am J Geriatr Cardiol. 2003 Sep-Oct;12(5):293-7 (Lower serum T3 in cardiac failure: The odds ratio for events was 9.8 (95% confidence interval,2.2-43, p=0.004) for patients in the lowest tertile of triiodothyronine, that is, lower than 80 ng/dL, compared with patients with levels above 80 ng/dL)
Division of Geriatric Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paolo, Brazil
Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med. 2005 Feb;118(2):132-6
Institute of Clinical Physiology, C.N.R., Pisa, Italy. [email protected]
Klein I, Ojama K. In: Werner & Ingbar’s The Thyroid, ed. Braverman LE & Utiger RD, Lippincott-Raven Publishers, Philadelphia, 1996, 62: 799-804

A low serum free T3 index/reverse T3 ratio in chronic heart failure patients is a highly significant predictor of poor outcome

Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M. Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg. 2003
Hamilton MA, Stevenson LW, Luu M, Walden JA. Altered thyroid hormone metabolism in advanced heart failure. J Am Coll Cardiol. 1990 Jul;16(1):91-5
Division of Cardiology, University of California, Los Angeles School of Medicine 90024-1679
Kozdag G, Ural D, Vural A, Agacdiken A, Kahraman G, Sahin T, Ural E, Komsuoglu B. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy. Eur J Heart Fail. 2005 Jan;7(1):113-8
Department of Cardiology, Kocaeli University, Yahyakaptan Mah. A4 Blok Daire:3, Kocaeli 41050, Turkey. [email protected]

A low serum T3 or T4 in heart patients is associated with an increased risk of cardiac arrest/death

Wortsman J, Premachandra BN, Chopra IJ, Murphy JE. Hypothyroxinemia in cardiac arrest. Arch Intern Med. 1987 Feb;147(2):245-8
Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-13

Cardiovascular disease and mortality isincreased in hypothyroidism (+ 70 % for both)

Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216
Department of Internal Medicine B, Ernst-Moritz-Arndt-University, Greifswald, Germany

Thyroid therapy ot cardiac patients

Corrective thyroid therapy is safe in patients with common benign cardiac arrhythmias (under the condition that thyroid treatment is started at low doses and then gradually and prudently increased to the adequate dose). The treatment does not trigger an increase in arrhythmia frequency except in rare patients with baseline atrial premature beats. It is, however, associated with an increase in basal, average and maximal heart rates

Polikar R, Feld GK, Dittrich HC, Smith J, Nicod P. Effect of thyroid replacement therapy on the frequency of benign atrial and ventricular arrhythmias. J Am Coll Cardiol. 1989 Oct;14(4):999-1002
Division of Cardiology, University of California, San Diego.

Thyroid therapy corrects the bradycardia of hypothyroidism

Yamauchi K, Takasu N, Ichikawa K, Yamada T, Aizawa T. Effects of long-term treatment with thyroxine on pituitary TSH secretion and heart action in patients with hypothyroidism. Acta Endocrinol (Copenh). 1984 Oct;107(2):218-24 (T4 doses should be adjusted to maintain normal ET/PEP (systolic time intervals) rather than normal serum TSH levels

Thyroid therapy corrects the ventricular arrhythmia

Vanin LN, Smetnev AS, Sokolov SF, Kotova GA, Masenko VP. Thyroid function in patients with ventricular arrhythmia. Kardiologiia. 1989 Feb;29(2):64-7 (Thyroid therapy for hypothyroidism led to the disappearance of paroxysms of ventricular tachycardia and reduced the total number and grades of ventricular extra-systoles in patients with ventricular arrhythmias; moreover, sensitivity to antiarrhythmic agents developed to replace an earlier resistance)

Coronary heart disease in humans: the improvement with thyroid treatment

Barnes BO. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancet. 1959 Aug 22;2:149-52
Holland FW 2nd, Brown PS Jr, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg. 1992 Aug;54(2):301-5
Israel M. An effective therapeutic approach to the control of atherosclerosis illustrating harmlessness of prolonged use of thyroid hormone in coronary disease. Am J Dig Dis. 1955 June;161-8
Yokohama et al, Cardiology, 1992, 81 (1): 34-45;

Adequate thyroxine replacement in hypothyroidism prevents coronary artery disease progression

Perk M, O’Neill BJ; The effect of thyroid therapy on angiographic artery disease progression . Can J Card. 1997;13(3):273-6

(Dessicated) thyroid therapy improves cardiac failure refractory to digitalis in humans

Zondek H. Myxedema Heart. Munch Med Wochenschr. 1918, 65: 1180-3
Khaleeli AA, Memon N. Factors affecting resolution of pericardial effusions in primary hypothyroidism: a clinical, biochemical and echocardiographic study. Postgrad Med J. 1982 Aug;58(682):473-6

T3-therapyimproves the outcome of open heart sugery, especially heart transplants

Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology. 1996 Nov-Dec;87(6):509-15.
Novitzky D, Cooper DK, Chaffin JS, Greer AE, DeBault LE, Zuhdi N. Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation. 1990 Feb;49(2):311-6

Thyroid hormone therapy greatly reduces the lesions of experimental myocardial infarct in rats

Holland FW, Brown PS, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg 1992 54: 301-305

Thyroid therapy reduces coronary artery disease and cardiac fibrosis in mice

Yao J, Eghbali M. Decreased collagen mRNA and regression of cardiac fibrosis in the ventricular myocardium of the tight skin mouse following thyroid hormone treatment. Cardiovasc Res. 1992 Jun;26(6):603-7

Thyroid therapy reduced the lesions of experimental cardiac arrest in dogs

Facktor MA, Mayor GH, Nachreiner RF, D’Alecy LG. Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs. Resuscitation. 1993 Oct;26(2):141-62

Thyroid therapy reduced the complications of hemorrhagic shock in dogs

Shigematsu H, Shatney CH. The effect of triiodothyronine (T3) and reverse triiodothyronine (rT3) on canine hemorrhagic shock. Nippon Geka Gakkai Zasshi. 1988 Oct;89(10):1587-93.

Thyroid Therapy and Bone Density

Studies with association between thyroid therapy and increased loss of bone density

Bone loss during thyroid treatment mainly occurs in HRT untreated postmenopausal women and who have a suppressed TSH, possibly being overtreated with thyroid hormones

Taelman P, Kaufman JM, Janssens X, Vandecauter H, Vermeulen A. Reduced forearm bone mineral content and biochemical evidence of increased bone turnover in women with euthyroid goitre treated with thyroid hormone. Clin Endocrinol (Oxf). 1990 Jul;33(1):107-17
Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med. 1990 Aug 15;113(4):265-9
Adlin EV, Maurer AH, Marks AD, Channick BJ. Bone mineral density in postmenopausal women treated with L-thyroxine. Am J Med. 1991 Mar;90(3):360-6
Paul TL, Kerrigan J, Kelly AM, Braverman LE, Baran DT. Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA. 1988;259:3137-41

Bone loss is mainly transitory only during the first year with no increased fracture incidence

Tremollieres F, Pouilles JM, Louvet JP, Ribot C. Transitory bone loss during substitution treatment for hypothyroidism. Results of a two year prospective study. Rev Rhum Mal Osteoartic. 1991 Dec;58(12):869-75
Ribot C, Tremollieres F, Pouilles JM, Louvet JP. Bone mineral density and thyroid hormone therapy. Clin Endocrinol (Oxf). 1990 Aug;33(2):143-53

Oestrogen therapy neutralizes, prevents bone loss induced by corrective thyroid therapy

45. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA 1994;271:1245-9

Studies where thyroid therapy does not cause or increase loss of bone density

43. Greenspan SL, Greenspan FS, Resnick NM, Block JE, Friedlander AL, Genant HK. Skeletal integrity in premenopausal and postmenopausal women receiving long-term L-thyroxine therapy Am J Med. 1991;91:5-14
44. Franklyn JA, Betteridge J, Daykin J, Holder R, Oates GD, Parle JV, Lilley J, Heath DA, Sheppard MC. Long-term thyroxine treatment and bone mineral density. Lancet. 1992 Jul 4;340(8810):9-13
Department of Medicine, University of Birmingham, UK
Eulry F, Bauduceau B, Lechevalier D, Magnin J, Crozes P, Flageat J, Gautier D. Bone density in differentiated cancer of the thyroid gland treated by hormone-suppressive therapy. Study based on 51 cases. Rev Rhum Mal Osteoartic. 1992 Apr;59(4):247-52
Grant DJ, McMurdo ME, Mole PA, Paterson CR, Davies RR. Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis. Clin Endocrinol (Oxf). 1993 Nov;39(5):529-33.

Studies where thyroid therapy improves bone formation

Svanberg E, Healey J, Mascarenhas D. Anabolic effects of rhIGF-I/IGFBP-3 in vivo are influenced by thyroid status. Eur J Clin Invest. 2001 Apr;31(4):329-36