This website is dedicated to the millions of thyroid patients who are being ignored and left to suffer unnecessarily, and to healthcare practitioners, who want to better serve those patients.

Thyroid Hormone References for Doctors

The reference list contains the major references of the pro and con studies on thyroid hormone therapy use, as it is important that physicians should be aware of these when debating with colleagues or other representatives of medical institutions. The reader should find the list particularly valuable in his/her researches. Whenever possible, the references regardomg human studies are mentioned in preference to those of animal studies. Senescence is associated with a decline of the thyroid axis Senescence is associated with reductions of the serum levels of TSH, T3 and T4

  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
  7. 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

Senescence is associated with a reduction of the metabolic clearance of thyroid hormones

  1. 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
  2. Katzeff HL. Increasing age impairs the thyroid hormone response to overfeeding. Proc Soc Exp Biol Med. 1990 Jul;194(3):198-203

Senescence is associated with a reduction of the amount of thyroid hormone (cellular) receptors

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

Senescence is associated with alterations of the circadian cycle of serum TSH: lower amplitude and phase advance

  1. 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
  2. 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

  1. Antipenko AYe, Antipenko YN. Thyroid hormones and regulation of cell reliability systems. Adv Enzyme Regul. 1994;34:173-98
  2. Tseng YL, Latham KR. Iodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation. Lipids. 1984 Feb;19(2):96-102
  3. 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
  4. 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
  5. 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
  6. 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

  1. 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

  1. 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

  1. Palmer KC, Mari F, Malian MS. Cadmium-induced acute lung injury: compromised repair response following thyroidectomy. Environ Res. 1986 Dec;41(2):568-84
  2. 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: thyroid hormones stimulate the immune system Low thyroid hormone levels are associated with immune deficiency

  1. 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
  2. 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
  3. 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
  4. 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

  1. 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
  2. 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
  3. 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
  4. Paavonen T. Enhancement of human B lymphocyte differentiation in vitro by thyroid hormone. Scand J Immunol. 1982 Feb;15(2):211-5
  5. 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
  6. 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
  7. 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
  8. 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
  9. Kvetny J, Matzen LE. Thyroid hormone induced oxygen consumption and glucose-uptake in human mononuclear cells. Thyroidology. 1989 Apr;1(1):5-9
  10. 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: thyroid hormones stimulate fibroblast proliferation and differentiation

  1. 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 thyoid dysfunction may increase the risk of phenotypic expression of other unfavourable gene polymorphisms

  1. 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
  2. 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

  1. 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
  2. Guimaraes V, DeGroot LJ. Moderate hypothyroidism in preparation for whole body 131I scintiscans and thyroglobulin testing. Thyroid. 1996 Apr;6(2):69-73
  3. Heitman B, Irizarry A. Hypothyroidism: common complaints, perplexing diagnosis. Nurse Pract. 1995 Mar;20(3):54-60
  4. 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
  5. 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

  1. 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
  2. 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
  3. 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
  4. 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.
  5. 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

  1. 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
  2. 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
  3. Gold MS, Pottash AL, Extein I. “Symptomless” autoimmune thyroiditis in depression. Psychiatry Res. 1982 Jun;6(3):261-9
  4. 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
  5. Howland RH. Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. J Clin Psychiatry. 1993 Feb;54(2):47-54
  6. 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
  7. 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
  8. 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
  9. 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
  10. Joffe RT, Marriott M. Thyroid hormone levels and recurrence of major depression. Am J Psychiatry. 2000 Oct;157(10):1689-91 (“the time to recurrence of major depression was inversely related to T3 levels but not to T4 levels”)

Depression: the improvement with thyroid treatment

  1. 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
  2. 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
  3. 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
  4. 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
  5. Prange AJ Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid. 1996 Oct;6(5):537-43
  6. 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
  7. 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
  8. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. Landen M, Baghaei F, Rosmond R, Holm G, Bjorntorp P, Eriksson E. Dyslipidemia and high waist-hip ratio in women with self-reported social anxiety. Psychoneuroendocrinology. 2004 Sep;29(8):1037-46 (Serum levels of free thyroxin (14+/-2 vs. 16+/-4, P=0.04) were lower in subjects confirming social anxiety)

Anxiety: the improvement with thyroid treatment

  1. 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
  2. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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, behavioral responsiveness and myocardial contractility. Minerva Endocrinol. 1991 Jul-Sep;16(3):113-8
  6. 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
  7. 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

  1. Monzon Monguilod MJ, Perez Lopez-Fraile I. Subclinical hypothyroidism as a cause of reversible cognitive deterioration. Neurologia. 1996 Nov;11(9):353-6
  2. 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
  3. 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
  4. 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

  1. 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
  2. Orr WC, Males JL, Imes NK. Myxedema and obstructive sleep apnea. Am J Med. 1981 May;70(5):1061-6
  3. 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

  1. 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

  1. 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
  2. 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

  1. 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
  2. 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
  3. Selenkow HA, Wool MS. A new synthetic hormone combination for clinical therapy. Ann Int Med. 1967 July, 67 (1): 90-9
  4. 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
  5. 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
  6. 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

  1. 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
  2. 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

  1. Papaioannou GI, Lagasse M, Mather JF, Thompson PD. Treating hypothyroidism improves endothelial function. Metabolism. 2004 Mar;53(3):278-9
  2. 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

  1. Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine. 2004 Jun;24(1):1-13
  2. 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
  3. 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
  4. 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

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

Coronary heart disease: the association with lower thyroid hormone levels

  1. 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

  1. Barnes BO. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancet. 1959 Aug 22;2:149-52
  2. 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
  3. 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
  4. 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)

  1. Dorr M, Volzke H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol. 2005 Dec;30(4):199-216

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

  1. 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
  2. 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

  1. 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
  2. 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
  3. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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

  1. 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
  2. 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
  3. Lamberg; B-A. Glucose metabolism in thyroid disease. Acta Med Scand. 1965178: 351
  4. 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

  1. Houssay BA. The thyroid and diabetes. Vitam Horm. 1946;4:188
  2. 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

  1. 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
  2. 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
  3. Neeck G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheumatol. 1992 Jul;19(7):1120-2
  4. 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;10(1):67-70

Rheumatism: the improvement with thyroid treatment

  1. Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on musculoskeletal symptoms. Clin Rheumatol. 1993 Sep;12(3):341-5
  2. 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

  1. 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

  1. Shelton BK. Hypothyroidism in cancer patients. Nurse Pract Forum. 1998 Sep;9(3):185-91
  2. 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
  3. Liechty RD, Hodges RD, Burket J. Cancer and thyroid function. JAMA. 1963 Jan 5;183:30-2.
  4. Tellini U, Pellizzari L, Pravadelli B. Thyroid function in elderly with neoplasms. Minerva Med. 1999 Apr;90(4):111-21
  5. 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?

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

Longevity: the association with thyroid hormone

  1. 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
  2. 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
  3. 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
  4. 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

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

  1. Ladenson PW. Optimal laboratory testing for diagnosis and monitoring of thyroid nodules, goiter, and thyroid cancer. Clin Chem. 1996 Jan;42(1):183-7

Serum TSH

  1. Nunez S, Leclere J. Diagnosis of hypothyroidism in the adult. Rev Prat. 1998; 48(18): 1993-8.
  2. 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
  3. 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
  4. Beth Israel Hospital, Boston
  5. 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

  1. 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.
  2. 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

  1. 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
  2. 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
  3. 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”)
  4. Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med. 1990; 113:450-4
  5. 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)

Serum TRH test

  1. 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
  2. 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
  3. 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
  4. 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. 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

Corrective Thyroid Therapy Thyroid medications

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

Thyroxine

  1. Oppenheimer JH, Braverman LE, Toft A, Jackson, IM, Ladenson, PW. Thyroid hormone treatment when and what? J Clin Endocrinol Metab. 1995;80:2873-83
  2. Dong BJ, Brown CH. Hypothyroidism resulting from generic levothyroxine failure. J Am Board Fam. Pract. l991;4:167-70
  3. Roti E, Minelli R, Gardini E, Braverman LE. The use of misuse of thyroid hormone. Endocrine Rev. 1993;14:401-23
  4. Toft AD. Thyroxine therapy. N Engl J Med. 1994 Jul 21;331(3):174-80
  5. USP Dispensing Information: Volume 1- Drug Information for Health Care Professionals. The United States Pharmacopeial Convention, Rockville, MD, 1997
  6. 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

  1. Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism. 1977 Nov;26(11):1213-8
  2. Mangieri CN, Lund MH. Potency of United States Pharmacopeia desiccated thyroid tablets as determined by the antigoitrogenic assay in rats. J Clin Endocrinol Metab. 1970 Jan;30(1):102-4
  3. Gaby AR. Sub-laboratory hypothyroidism and the empirical use of Armour thyroid. Altern Med Rev. 2004 Jun;9(2):157-79
  4. 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
  5. 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 hormone treatment

  1. Kaufman SC, Gross GP, Kennedy DL. Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1997; 1:285-91
  2. . 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 treatment: dosage

  1. 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
  2. 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
  3. 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
  4. Kabadi UM. Optimal daily levothyroxine dose in primary hypothyroidism. Its relation to pre-treatment thyroid hormone indexes. Arch Intern Med. 1990;149:2209-12
  5. 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
  6. Kaplan MM. Monitoring thyroxine treatment during pregnancy. Thyroid. 1992:2:147-52
  7. Singer PA. Thyroiditis acute, subacute, and chronic. Med Clin North Am. 1991:75:61-77
  8. 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
  9. 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
  10. Fisher DA. Management of congenital hypothyroidism. J Clin Endocrinol Metab 1991;72:523-9
  11. Bearcoft CP, Toms GC, Williams SJ, Noonan K, Monson JP. Thyroxine replacement in post-radioiodine hypothyroidism. Clin Endocrinol. 1991;34:115-8

Thyroid treatment: thyroid hormone absorption and malabsorption

  1. Hays MT, Nielsen KRK. Human thyroxine absorption: age effects and methodological analyses. Thyroid. 1994:4:55-64
  2. Wenzel KW, Kirscheiper HE. Aspects of the absorption of oral 1-thyroxine in normal man. Metabolism. 1977;26:1-8
  3. Benvenga S, Bartolone L, Squadrito S, Lo Giudice F, Trimarchi F. Delayed intestinal absorption of levothyroxine. Thyroid. 1995;5(4):249-53
  4. Read DG, Hays MT, Hershman JM. Absorption of oral thyroxine in hypothyroid and normal man. J Clin Endocrinol Metab. 1970;30:798-9
  5. Azizi F, Belur R, Albano J. Malabsorption of thyroid hormones after jejunoileal bypass for obesity. Ann Intern Med. 1979;90:941-2
  6. Bevan JS, Munro JF. Thyroxine malabsorption following intestinal bypass surgery. Int J Obes. 1986; 10:245-6
  7. 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
  8. Ain KB, Refetoff S, Fein HG, Weintraub BD. Pseudomalabsorption of levothyroxine. JAMA 1991;266:2118-20
  9. Northcutt RC, Stiel JN, Hollifiels JW, Stant EG. The influence of cholestyramine on thyroxine absorption. JAMA. 1969;208:1857-61
  10. Harmon SM, Siefert CF. Levothyroxine-cholestyramine interaction reemphasized. Ann Intern Med. 1991;115:658-9
  11. Sperber AD, Liel Y. Evidence for interface with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med 1992; 152:183-4
  12. 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
  13. Sherman SI, Tielens E, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. Am J Med. 1994;96:531-5
  14. 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

  1. Klein I, Ojamaa K. Thyroid hormone and the heart. Am J Med. 1996;101:459-60
  2. Keating FR, Parkin TW, Selby JB, Dickinson LS. Treatment of heart disease associated with myxedema. Prog Cardiovasc Dis. 1960;3:364-81
  3. 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
  4. Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med. 1984;77:261-6
  5. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA. 1994;271:1245-9
  6. 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
  7. 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
  8. Magner J, Gerber P. Urticaria due to blue dye in synthroid tablets. Thyroid. 1994 Fall;4(3):341

Thyroid treatment: interferences or associations

  1. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer. Ann Intern Med. 1994; 121:247-51
  2. Rosenbaum RL, Barzel US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med. 1982:96:53-5
  3. 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

  1. 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
  2. Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med. 1990; 113:450-4
  3. 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
  4. 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

DISCUSSIONS ON THYROID DIAGNOSIS SERUM TSH: IS THE TSH SERUM MEASUREMENT ALONE 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) of the patient. Article defending the serum TSH test as the first line approach to diagnose thyroid dysfunction

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

Doubts on the usefulness of the serum TSH test alone for diagnosis Overreliance on laboratory tests without clinical evaluation may lead to considerable diagnostic errors

  1. Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assay. J Clin Endocrinol Metab. 1990;71:553-8.
  2. De Los Santos ET, Mazzaferri EL. Sensitive thyroid-stimulating hormone assays: Clinical applications and limitations. Compr Ther. 1988; 14(9): 26-33.
  3. 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”)
  4. Rippere V. Biochemical victims: False negative diagnosis through overreliance on laboratory results—a personal report. Med Hypotheses. 1983; 10(2): 113.

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

  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 (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!)
  2. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
  3. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8 (remarkable article of which a lot of the following information is extracted)
  4. 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
  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
  6. Ringel MD, Mazzaferri EL. Editorial: subclinical thyroid dysfunction: can there be a consensus about the consensus? J Clin Endocrinol Metab. 2005;90:588–90
  7. Pinchera A. Subclinical thyroid disease: to treat or not to treat? Thyroid. 2005;15:1–2

Studies that show that the serum TSH reference range of 0.1-5.1 mU/liter for a POPULATION is too large Studies indicating a population mean value of 1.5 mU/liter for an iodine-sufficient population

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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

A longitudinal study in diabetics where a baseline TSH levels above the 1.53 mU/liter predicted subsequent thyroid dysfunction, whereas no thyroid dysfunction if TSH levels < 1.53 mU/liter, the reference range for diabetics should then be 0.4-1.52 mU/liter

  1. 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

If the serum TSH reference range would be based upon a cohort of truly normal individuals with no personal or family history of thyroid dysfunction, no visible or palpable goiter, not taking any medication, who are seronegative for thyroid preoxidase antibodies, and whose blood samples are drawn fasting in the morning hours (06–10 h), the TSH reference range would become 0.4–2.5 mU/L (Demers & co, Baloch & co.)

  1. 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
  2. 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
  3. 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

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. This tighter reference range may certainly be more applicable to African-Americans, who have a lower mean TSH

  1. 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
  2. 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

Publications with data to support a more narrow reference range for serum TSH that would be obtained when persons with diffuse hypoechogenicity of the thyroid on ultrasound, a condition that precedes thyroid peroxidase antibody positivity in autoimmune thyroid disease, would be excluded

  1. 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

For the American Association of Clinical Endocrinologists the revised reference TSH range is 0.3–3.0 mU/L

  1. 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

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). ForAfrican-Americans, the TSH reference range should therefore be lower than in whites

  1. 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 serum TSH cut-off point between hypo- and euthyroidism is 2, not 4 or 5.5

  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 Feb;138(2):141-5(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)

In 2003, the National Academy of Clinical Biochemistry (NACB) has reduced 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

  1. 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

Supporters of the recommendations of the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, American Thyroid Association) promote a target TSH range of 1.0–1.5 mU/liter in patients already receiving T4 therapy

  1. 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

  1. 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
  2. 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
  3. 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
  4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  5. 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
  6. 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
  7. 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

The TSH reference range for an INDIVIDUAL is narrower than the reference range for a population The value of a population-based reference range is limited when the individual patient-based reference range (i.e. his personal reference range) is narrow

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

The 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 (as explained by Wartofsky 2005)

  1. 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 have data to support that each of us has a genetically determined optimal free T4 (FT4)-TSH set point or relationship

  1. 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
  2. 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 that s/he becomes hypothyroid or hyperthyroid.

  1. 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 (as explained by Wartofsky 2005)

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

There is a 3-fold difference between the average daily maximal TSH (3) and minimal TSH (1 mIU/ml)

  1. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B,
  2. 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

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

  1. Pain RW. Simple modifications of three routine in vitro tests of thyroid function. Clin Chem. 1976; 22(10): 1715-8.
  2. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
  3. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8

Other arguments that may explain why the TSH test alone is not the only test The TSH test is insufficient to diagnose all forms of hypothyroidism, including the borderline forms. The frequency of abnormal TSH values

  1. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  2. 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

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!): they have to be treated

  1. 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
  2. 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
  3. 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
  4. Kabadi UM. ‘Subclinical hypothyroidism:’ natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957-61

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.

  1. 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
  2. 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.
  3. 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.

  1. 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

  1. 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
  2. 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
  3. 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
  4. 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

Necessity for other tests than the TSH to diagnosis thyroid dysfunction, e.g. the serum free T4

  1. 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

  1. 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
  2. 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): 129-3

Conditions or factors that DEPRESS the serum TSH Aging

  1. Urban RJ. Neuroendocrinology of aging in the male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31
  2. 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

  1. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff OA. Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab. 1977; 45: 560
  2. 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
  3. 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
  4. 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

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

Pregnancy (first trimester)

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

Depression and anxiety disorders

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990; 46(8): 591-9
  2. 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
  3. 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
  4. 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
  5. 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
  6. Adriaanse R, Brabant G, Endert E, Wiersinga W. Pulsatile thyrotropin secretion in patients with Cushing’s syndrome. Metabolism. 1994 Jun;43(6):782-6
  7. Beyer HK-, Schuster P, Pressler H. Studies on hypothalamic pituitary thyroid regulation in hemodialysis patients. Nuklearmedizin 1981;20(1):19-24
  8. 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
  9. 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
  10. 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.
  11. Wintemitz WW, Dzur JA. Pituitary failure secondary to head trauma. Case report. J Neurosurg. 1976; 44(4): 504-5
  12. Dzur JA, Wintemitz WW. Posttraumatic hypopituitarism: Anterior pituitary insufficiency secondary to head trauma. South Med J. 1976; 69(10): 1377-9
  13. 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
  14. 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
  15. Bacci V, Schussler GC, Kaplan TB. The relationschip between serum triidothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab. 1982; 54:1229-35
  16. 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
  17. 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.

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metabol. 1974;39:923-7
  9. 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.
  10. 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.
  11. 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
  12. 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
  13. 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.
  14. 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
  15. 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
  16. Samuels MH, Kramer P, Wilson D, Sexton F. Effect ofnaloxone infusions on pulsatile thyrotropin secretion. J Clin Endocrinol Metab. 1994;78(5):129-32.
  17. 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
  18. 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
  19. 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

  1. 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.
  2. 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
  3. 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

  1. 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
  2. Yeo PP, Loh KC. Subclinical thyrotoxicosis. Adv Intern Med. 1998; 43: 501-32
  3. Chanson P. Insuffisance thyrotropic. Rev Prat. 1998 15; 48(18): 2023-6
  4. 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.
  5. 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

  1. 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
  2. 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.
  3. 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
  4. 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
  5. 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
  6. Sjoberg S, Wemer S. Increased level of TSH can be a sign of adrenal cortex failures: Not necessarily of thyroid gland disease. Lakartidningen 1999; 96(5):464-5
  7. 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
  8. 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.

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8):591-9
  2. 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
  3. 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
  4. 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

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8): 591-9
  2. 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
  3. Volpe R. Subacute (de Quervain’s) thyroiditis. J Clin Endocrinol Metab. 1979 Mar;8(1):81-95
  4. 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
  5. 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)

  1. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. Rose SR, Nisula BC. Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab. 1989; 68(6):1086-90
  6. 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
  7. 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

  1. Beck-Peccoz P, Persani L. Variable biological activity of thyroid stimulating hormone. Eur J Endocrinol. 1994 Oct;131(4):331-40
  2. 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
  3. 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

  1. 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
  2. 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
  3. 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
  4. 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
  5. Laurberg P. Persistent problems with the specificity of immunometric TSH assays. Thyroid. 1993 Winter;3(4):279-83
  6. 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
  7. 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
  8. Spencer CA, Challand GS. Interference in a radioimmunoassay for human thyrotropin. Clin Chem 1977;23(3): 584-8
  9. 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
  10. 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
  11. 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)
  12. 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
  13. 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
  14. 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
  15. 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

Doubts on the adequateness of measuring the serum TSH as a help to monitor a thyroid treatment ( follow-up) The serum TSH test for follow-up: The risk of misinterpretation increases when monitoring the treatment of hyper- or hypothyroidism

  1. 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, aundetectable serum TSH is found

  1. 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
  2. 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 9 hours after intake

  1. 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 patients who exhibit reversion of an initially high TSH level back into the reference range, are found tsubsequently develop mild thyroid failure

  1. 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

  1. 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

  1. 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
  2. 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
  3. 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
  4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  5. 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
  6. 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
  7. 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

Other tests : urinary T3 as a complementary test

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

DISCUSSIONS ON THYROID TREATMENT DOES THYROID TREATMENT DEFINITELY SUPPRESS THE THYROID GLAND? No, after stopping thyroid medications, the thyroid axis recovers its initial condition in 2 to 3 weeks on the average

  1. 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)
  2. 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.”)
  3. 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.”)
  4. 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”).
  5. 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
  6. Johnston MW, Squires AH, Farquharson RF. The effect of prolonged administration of thyroid. Ann Intern Med. 1951 Nov;35(5):1008-22
  7. Riggs DS, Man EB, Winkler AW. Serum iodine of euthyroid subjects treated with desiccated thyroid. J Clin Invest. 1945;24:722-31
  8. 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

  1. 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)

MILD THYROID FAILURE: TO TREAT OR NOT TO TREAT Arguments pro thyroid treatment of mild thyroid failure 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!): they have to be treated

  1. 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
  2. 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
  3. 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
  4. Kabadi UM. ‘Subclinical hypothyroidism:’ natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957-61

MILD THYROID FAILURE: TO TREAT OR NOT TO TREAT Arguments pro thyroid treatment of mild thyroid failure 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!): they have to be treated

  1. 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
  2. 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
  3. Cooper DS 2001 Subclinical hypothyroidism. N Engl J Med 345:260–5
  4. Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44–50
  5. 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
  2. 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
  3. Faber J, Petersen L, Wiinberg N, Schifter S, Mehisen J. Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid. 2002; 12:319–24
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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 important to treat mild thyroid failure to avoid adverse physical and psychological consequences

  1. 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
  2. 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
  3. Joffe RT, Levitt AJ 1992 Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 17:215–21
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  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Misiunas A, Ravera HN, Faraj G, Faure E. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995;5:283–6
  11. 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
  12. 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
  13. 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
  14. Foundation for Blood Research, Scarborough, ME 04074, USA
  15. 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
  16. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med. 1984;101:18–24
  17. 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)
  18. 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
  19. 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
  20. Kahaly GJ 2000 Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 10:665–79
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. Perk M, O’Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997;13:273–
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  36. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA. 1996;276:285–92
  37. 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
  38. 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 relaxation and a decrease in the compliance to the ventricular filling… Several significant correlations were found between the parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis.”)

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

  1. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24

Important frequency of subclinical hypothyroidism:

  1. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG,
  2. 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
  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA. 1987 ;258:209–13
  12. 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”)

Important risk of progression into overt hypothyrodism

  1. 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
  2. Bastenie PA, Bonnyns M, Vanhaelst L. Natural history of primary myxedema. Am J Med. 1985;79:91–100
  3. Kabadi UM. Subclinical hypothyroidism. Natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957–61
  4. 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
  5. 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
  6. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am. 1997;26:189–218
  7. 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

  1. 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 it is important to treat mild glandular failure that causes other diseases such as diabetes and hypertension

  1. 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
  2. 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
  3. Dluhy RG, Williams GH. Aldosterone: villain or bystander? N Engl J Med. 2004;351:8–10

Arguments contra thyroid treatment of mild thyroid failure

  1. Chu JW, Crapo LM. Should mild hypothyroidism be treated? Am J Med. 2002;112:422–3
  2. 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 inappropriatebecause it results in overtreatment with attendant risks of subclinical hyperthyroidism. (citic: 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
  2. 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 treatment does not improve clinically hypothyroid patients who have normal tests (critic: but possibly T3-T4 does)

  1. 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;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) a TSH 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)

  1. 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

  1. 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

  1. There is an equal concern about correct diagnosis and treatment of patients with TSH levels that are slightly below the reference interval because of risks to both heart and bone
  2. 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
  3. 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
  4. Stathatos N, Wartofsky L. Effects of thyroid hormone on bone. Clin Rev Bone Miner Metab. 2004;2:135–50

See also – http://www.intlhormonesociety.org/r…hyroid_biochemically_hypothyroid_patients.pdf

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