Endocrinol Metab.  2022 Apr;37(2):208-219. 10.3803/EnM.2022.1463.

Thyroid Function across the Lifespan: Do Age-Related Changes Matter?

• Walsh JP

• KMID: 2529212
• DOI: http://doi.org/10.3803/EnM.2022.1463

Abstract

Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence. Pituitary-thyroid axis setpoints are probably established in utero, with maturation of thyroid function continuing until late gestation. From neonatal life (characterized by a surge of TSH and T4 secretion) through childhood and adolescence (when free triiodothyronine levels are higher than in adults), thyroid function tests display complex, dynamic patterns which are sexually dimorphic. In later life, TSH increases with age in healthy older adults without an accompanying fall in free T4, indicating alteration in TSH setpoint. In view of this, and evidence that mild subclinical hypothyroidism in older people has no health impact, a strong case can be made for implementation of age-related TSH reference ranges in adults, as is routine in children.

Keyword

Thyroid; Thyroid hormones; Thyrotropin; Genetics; Epigenomics; Growth and development; Aging; Reference values; Hypothyroidism

Figure

• 

  Fig. 1. Longitudinal changes in thyrotropin (TSH), free triiodothyronine (T3), and free thyroxine (T4) in adolescent males and females. Results are visualized using generalized additive models fitted to the unadjusted data. Mean values and 95% confidence bands are illustrated by solid and dotted lines respectively. Reproduced from Campbell et al. [60], with permission from Oxford University Press.

• 

  Fig. 2. Thyrotropin (TSH) and free thyroxine (T4) relationship analyzed by age in 120,403 patients who were not taking thyroxine treatment. The median TSH for each free T4 integer value (in pmol/ L) was calculated, then plotted as 20-year age bands in adults. The youngest age band (1 to 19 years) is not depicted because there were insufficient data to calculate median TSH for each free T4 value reliably; for clarity, interquartile ranges are not shown. Dotted horizontal and vertical lines mark the TSH reference range (0.4 to 4.0 mU/L) and free T4 reference range (10 to 20 pmol/L), respectively. Reproduced from Hadlow et al. [72], with permission from Oxford University Press.

Reference

1. Feingold KR, Anawalt B, Boyce A. South Dartmouth: MDText.com; 2000. Chapter, Ontogeny, anatomy, metabolism and physiology of the thyroid. 2011. [cited 2022 Apr 5]. Available from: www.endotext.org.

2. Gudernatsch JF. Feeding experiments on tadpoles. 1. The influence of specific organs given as food on growth and differentiation: a contribution to the knowledge of organs with internal secretion. Arch Entwicklngsrnechn Organ. 1912; 35:457–84.

3. Allen BM. The results of thyroid removal in the larvae of Rana pipiens. J Exp Zool. 1918; 24:499–519.

4. Sharp PJ. Photoperiodic regulation of seasonal breeding in birds. Ann N Y Acad Sci. 2005; 1040:189–99.

5. Dardente H, Hazlerigg DG, Ebling FJ. Thyroid hormone and seasonal rhythmicity. Front Endocrinol (Lausanne). 2014; 5:19.

6. Peters C, van Trotsenburg AS, Schoenmakers N. Diagnosis of endocrine disease: congenital hypothyroidism: update and perspectives. Eur J Endocrinol. 2018; 179:R297–317.

7. Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012; 366:243–9.

8. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002; 87:1068–72.

9. Dayan CM, Saravanan P, Bayly G. Whose normal thyroid function is better: yours or mine? Lancet. 2002; 360:353.

10. Szkudlinski MW, Fremont V, Ronin C, Weintraub BD. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev. 2002; 82:473–502.

11. Estrada JM, Soldin D, Buckey TM, Burman KD, Soldin OP. Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. Thyroid. 2014; 24:411–23.

12. Kempers MJ, van Trotsenburg AS, van Tijn DA, Bakker E, Wiedijk BM, Endert E, et al. Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism. J Clin Endocrinol Metab. 2005; 90:4094–100.

13. Bagattini B, Cosmo CD, Montanelli L, Piaggi P, Ciampi M, Agretti P, et al. The different requirement of L-T4 therapy in congenital athyreosis compared with adult-acquired hypothyroidism suggests a persisting thyroid hormone resistance at the hypothalamic-pituitary level. Eur J Endocrinol. 2014; 171:615–21.

14. Hansen PS, Brix TH, Sorensen TI, Kyvik KO, Hegedus L. Major genetic influence on the regulation of the pituitarythyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab. 2004; 89:1181–7.

15. Samollow PB, Perez G, Kammerer CM, Finegold D, Zwartjes PW, Havill LM, et al. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab. 2004; 89:3276–84.

16. Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol (Oxf). 2008; 68:652–9.

17. Alul FY, Cook DE, Shchelochkov OA, Fleener LG, Berberich SL, Murray JC, et al. The heritability of metabolic profiles in newborn twins. Heredity (Edinb). 2013; 110:253–8.

18. Nolan J, Campbell PJ, Brown SJ, Zhu G, Gordon S, Lim EM, et al. Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3. Eur J Endocrinol. 2021; 185:743–53.

19. Kus A, Chaker L, Teumer A, Peeters RP, Medici M. The genetic basis of thyroid function: novel findings and new approaches. J Clin Endocrinol Metab. 2020; 105:dgz225.

20. Teumer A, Chaker L, Groeneweg S, Li Y, Di Munno C, Barbieri C, et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat Commun. 2018; 9:4455.

21. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009; 461:747–53.

22. Taylor PN, Porcu E, Chew S, Campbell PJ, Traglia M, Brown SJ, et al. Whole-genome sequence-based analysis of thyroid function. Nat Commun. 2015; 6:5681.

23. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012; 13:97–109.

24. Trerotola M, Relli V, Simeone P, Alberti S. Epigenetic inheritance and the missing heritability. Hum Genomics. 2015; 9:17.

25. Lafontaine N, Campbell PJ, Castillo-Fernandez JE, Mullin S, Lim EM, Kendrew P, et al. Epigenome-wide association study of thyroid function traits identifies novel associations of fT3 with KLF9 and DOT1L. J Clin Endocrinol Metab. 2021; 106:e2191–202.

26. Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol. 2015; 3:286–95.

27. Knudsen N, Bulow I, Jorgensen T, Laurberg P, Ovesen L, Perrild H. Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status. Eur J Endocrinol. 2000; 143:485–91.

28. Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med. 2006; 354:2783–93.

29. Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Pedersen IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol. 2011; 7:232–9.

30. van de Ven AC, Netea-Maier RT, Smit JW, Kusters R, van der Stappen JW, Pronk-Admiraal CJ, et al. Thyrotropin versus age relation as an indicator of historical iodine intake. Thyroid. 2015; 25:629–34.

31. Park SY, Kim HI, Oh HK, Kim TH, Jang HW, Chung JH, et al. Age- and gender-specific reference intervals of TSH and free T4 in an iodine-replete area: data from Korean National Health and Nutrition Examination Survey IV (2013-2015). PLoS One. 2018; 13:e0190738.

32. Fisher DA. Physiological variations in thyroid hormones: physiological and pathophysiological considerations. Clin Chem. 1996; 42:135–9.

33. Ehrenkranz J, Bach PR, Snow GL, Schneider A, Lee JL, Ilstrup S, et al. Circadian and circannual rhythms in thyroid hormones: determining the TSH and free T4 reference intervals based upon time of day, age, and sex. Thyroid. 2015; 25:954–61.

34. Wang D, Cheng X, Yu S, Qiu L, Lian X, Guo X, et al. Data mining: seasonal and temperature fluctuations in thyroidstimulating hormone. Clin Biochem. 2018; 60:59–63.

35. Yoshihara A, Noh JY, Watanabe N, Iwaku K, Kunii Y, Ohye H, et al. Seasonal changes in serum thyrotropin concentrations observed from big data obtained during six consecutive years from 2010 to 2015 at a single hospital in Japan. Thyroid. 2018; 28:429–36.

36. Ikegami K, Refetoff S, Van Cauter E, Yoshimura T. Interconnection between circadian clocks and thyroid function. Nat Rev Endocrinol. 2019; 15:590–600.

37. Kuzmenko NV, Tsyrlin VA, Pliss MG, Galagudza MM. Seasonal variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis. Chronobiol Int. 2021; 38:301–17.

38. Kim TH, Kim KW, Ahn HY, Choi HS, Won H, Choi Y, et al. Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status. J Clin Endocrinol Metab. 2013; 98:3420–9.

39. Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf). 2013; 79:145–51.

40. Asvold BO, Bjoro T, Nilsen TI, Vatten LJ. Tobacco smoking and thyroid function: a population-based study. Arch Intern Med. 2007; 167:1428–32.

41. Thorpe-Beeston JG, Nicolaides KH, McGregor AM. Fetal thyroid function. Thyroid. 1992; 2:207–17.

42. Szinnai G, Lacroix L, Carre A, Guimiot F, Talbot M, Martinovic J, et al. Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. J Clin Endocrinol Metab. 2007; 92:70–6.

43. Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017; 144:2123–40.

44. LaFranchi SH. Thyroid function in preterm/low birth weight infants: impact on diagnosis and management of thyroid dysfunction. Front Endocrinol (Lausanne). 2021; 12:666207.

45. Korevaar TIM, Medici M, Visser TJ, Peeters RP. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol. 2017; 13:610–22.

46. Feingold KR, Anawalt B, Boyce A. Endotext. South Dartmouth: MDText.com; 2000. Chapter, Disorders of the thyroid gland in infancy, childhood and adolescence. 2011. [cited 2022 Apr 5]. Available from: www.endotext.org.

47. Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med. 1991; 324:532–6.

48. Hume R, Simpson J, Delahunty C, van Toor H, Wu SY, Williams FL, et al. Human fetal and cord serum thyroid hormones: developmental trends and interrelationships. J Clin Endocrinol Metab. 2004; 89:4097–103.

49. Williams FL, Simpson J, Delahunty C, Ogston SA, Bongers-Schokking JJ, Murphy N, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab. 2004; 89:5314–20.

50. Persani L, Borgato S, Romoli R, Asteria C, Pizzocaro A, Beck-Peccoz P. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab. 1998; 83:2486–92.

51. Gasparoni P, Rubello D, Persani L, Beck-Peccoz P. Unusual association between a thyrotropin-secreting pituitary adenoma and a papillary thyroid carcinoma. Thyroid. 1998; 8:181–3.

52. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med. 1989; 321:13–6.

53. Fisher DA, Odell WD, Hobel CJ, Garza R. Thyroid function in the term fetus. Pediatrics. 1969; 44:526–35.

54. Legakis I, Adamopoulos D, Stamatiou I, Gryparis A, Chrousos GP. Divergent patterns of thyrotropin and other thyroidal parameters in relationship with the sex of healthy neonates and infants less than two years old: a longitudinal study. Thyroid. 2019; 29:920–7.

55. Chan MK, Seiden-Long I, Aytekin M, Quinn F, Ravalico T, Ambruster D, et al. Canadian Laboratory Initiative on Pediatric Reference Interval Database (CALIPER): pediatric reference intervals for an integrated clinical chemistry and immunoassay analyzer, Abbott ARCHITECT ci8200. Clin Biochem. 2009; 42:885–91.

56. Murphy N, Hume R, van Toor H, Matthews TG, Ogston SA, Wu SY, et al. The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life. J Clin Endocrinol Metab. 2004; 89:2824–31.

57. Wide L, Eriksson K. Unique pattern of N-glycosylation, sialylation, and sulfonation on TSH molecules in serum of children up to 18 months. J Clin Endocrinol Metab. 2019; 104:4651–9.

58. Onsesveren I, Barjaktarovic M, Chaker L, de Rijke YB, Jaddoe VW, van Santen HM, et al. Childhood thyroid function reference ranges and determinants: a literature overview and a prospective cohort study. Thyroid. 2017; 27:1360–9.

59. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014; 24:1670–751.

60. Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020; 105:dgz331.

61. Antalis CJ, Stevens LJ, Campbell M, Pazdro R, Ericson K, Burgess JR. Omega-3 fatty acid status in attention-deficit/ hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids. 2006; 75:299–308.

62. Wilken JA, Greenspan LC, Kushi LH, Voss RW, Windham GC. Thyroid hormones and timing of pubertal onset in a longitudinal cohort of females, Northern California, 2006-11. Paediatr Perinat Epidemiol. 2016; 30:285–93.

63. Gunapalasingham G, Frithioff-Bojsoe C, Lund MA, Hedley PL, Fonvig CE, Dahl M, et al. Reference values for fasting serum concentrations of thyroid-stimulating hormone and thyroid hormones in healthy Danish/North-European white children and adolescents. Scand J Clin Lab Invest. 2019; 79:129–35.

64. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thyroid. Endocr Rev. 1995; 16:686–715.

65. Chahal HS, Drake WM. The endocrine system and ageing. J Pathol. 2007; 211:173–80.

66. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92:4575–82.

67. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), 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.

68. Bremner AP, Feddema P, Leedman PJ, Brown SJ, Beilby JP, Lim EM, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012; 97:1554–62.

69. Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab. 2012; 97:3944–50.

70. Chaker L, Korevaar TI, Medici M, Uitterlinden AG, Hofman A, Dehghan A, et al. Thyroid function characteristics and determinants: the Rotterdam Study. Thyroid. 2016; 26:1195–204.

71. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, FeldtRasmussen U, Henry JF, et al. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003; 13:3–126.

72. Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T4 in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab. 2013; 98:2936–43.

73. Wehmann RE, Nisula BC. Radioimmunoassay of human thyrotropin: analytical and clinical developments. Crit Rev Clin Lab Sci. 1984; 20:243–83.

74. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. 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.

75. Spencer CA, LoPresti JS, Patel A, Guttler RB, Eigen A, Shen D, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab. 1990; 70:453–60.

76. Hoermann R, Eckl W, Hoermann C, Larisch R. Complex relationship between free thyroxine and TSH in the regulation of thyroid function. Eur J Endocrinol. 2010; 162:1123–9.

77. Clark PM, Holder RL, Haque SM, Hobbs FD, Roberts LM, Franklyn JA. The relationship between serum TSH and free T4 in older people. J Clin Pathol. 2012; 65:463–5.

78. Jansen SW, Akintola AA, Roelfsema F, van der Spoel E, Cobbaert CM, Ballieux BE, et al. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism. Sci Rep. 2015; 5:11525.

79. Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010; 95:496–502.

80. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005; 90:5483–8.

81. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005; 90:5489–96.

82. Brabant G, Beck-Peccoz P, Jarzab B, Laurberg P, Orgiazzi J, Szabolcs I, et al. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol. 2006; 154:633–7.

83. Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011; 21:5–11.

84. Kahapola-Arachchige KM, Hadlow N, Wardrop R, Lim EM, Walsh JP. Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. Clin Endocrinol (Oxf). 2012; 77:773–9.

85. Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS). J Clin Endocrinol Metab. 2013; 98:1147–53.

86. Farrell CL, Nguyen L, Carter AC. Data mining for age-related TSH reference intervals in adulthood. Clin Chem Lab Med. 2017; 55:e213–5.

87. Mokhtar KM. TSH continuous reference intervals by indirect methods: a comparisons to partitioned reference intervals. Clin Biochem. 2020; 85:53–6.

88. Raverot V, Bonjour M, Abeillon du Payrat J, Perrin P, Roucher-Boulez F, Lasolle H, et al. Age- and sex-specific TSH upper-limit reference intervals in the general French population: there is a need to adjust our actual practices. J Clin Med. 2020; 9:792.

89. Vesper HW, Van Uytfanghe K, Hishinuma A, Raverot V, Patru MM, Danilenko U, et al. Implementing reference systems for thyroid function tests: a collaborative effort. Clin Chim Acta. 2021; 519:183–6.

90. Meyerovitch J, Rotman-Pikielny P, Sherf M, Battat E, Levy Y, Surks MI. Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. Arch Intern Med. 2007; 167:1533–8.

91. Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med. 2014; 174:32–9.

92. Livadas S, Bothou C, Androulakis I, Boniakos A, Angelopoulos N, Duntas L. Levothyroxine replacement therapy and overuse: a timely diagnostic approach. Thyroid. 2018; 28:1580–6.

93. Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010; 95:186–93.

94. Thayakaran R, Adderley NJ, Sainsbury C, Torlinska B, Boelaert K, Sumilo D, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ. 2019; 366:l4892.

95. Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RG, et al. Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidism. JAMA. 2019; 322:1977–86.

96. Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RG, Mooijaart SP, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017; 376:2534–44.

97. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004; 292:2591–9.

98. Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009; 94:1251–4.

99. Atzmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab. 2009; 94:4768–75.

100. Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frolich M, de Craen AJ, et al. Familial longevity is associated with decreased thyroid function. J Clin Endocrinol Metab. 2010; 95:4979–84.

101. Pearce SH, Razvi S, Yadegarfar ME, Martin-Ruiz C, Kingston A, Collerton J, et al. Serum thyroid function, mortality and disability in advanced old age: the Newcastle 85+ Study. J Clin Endocrinol Metab. 2016; 101:4385–94.

102. Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010; 304:1365–74.

103. Moon S, Kim MJ, Yu JM, Yoo HJ, Park YJ. Subclinical hypothyroidism and the risk of cardiovascular disease and allcause mortality: a meta-analysis of prospective cohort studies. Thyroid. 2018; 28:1101–10.

104. Moon S, Kong SH, Choi HS, Hwangbo Y, Lee MK, Moon JH, et al. Relation of subclinical hypothyroidism is associated with cardiovascular events and all-cause mortality in adults with high cardiovascular risk. Am J Cardiol. 2018; 122:571–7.

105. Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012; 172:811–7.

106. Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol Metab. 2008; 93:2998–3007.

107. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008; 29:76–131.

108. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012; 22:1200–35.

109. Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013; 2:215–28.

110. Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019; 322:153–60.

111. Cappola AR. The thyrotropin reference range should be changed in older patients. JAMA. 2019; 322:1961–2.