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

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.

[1]  N. Martin,et al.  Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3. , 2021, European journal of endocrinology.

[2]  S. Lafranchi Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction , 2021, Frontiers in Endocrinology.

[3]  A. Hishinuma,et al.  Implementing reference systems for thyroid function tests - A collaborative effort. , 2021, Clinica chimica acta; international journal of clinical chemistry.

[4]  M. Galagudza,et al.  Seasonal variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis , 2021, Chronobiology international.

[5]  A. McRae,et al.  Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L. , 2021, The Journal of clinical endocrinology and metabolism.

[6]  K. M. Mokhtar TSH continuous reference intervals by indirect methods: A comparisons to partitioned reference intervals. , 2020, Clinical biochemistry.

[7]  A. Teumer,et al.  The Genetic Basis of Thyroid Function: Novel Findings and New Approaches. , 2020, The Journal of clinical endocrinology and metabolism.

[8]  F. Borson‐Chazot,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 , 2020, Journal of clinical medicine.

[9]  N. Martin,et al.  Changes in thyroid function across adolescence: a longitudinal study. , 2020, The Journal of clinical endocrinology and metabolism.

[10]  P. Langhorne,et al.  Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. , 2019, JAMA.

[11]  A. Cappola The Thyrotropin Reference Range Should Be Changed in Older Patients. , 2019, JAMA.

[12]  L. Wide,et al.  Unique pattern of N-glycosylation, sialylation and sulfonation on TSH molecules in serum of children up to 18 months. , 2019, The Journal of clinical endocrinology and metabolism.

[13]  K. Toulis,et al.  Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study , 2019, BMJ.

[14]  E. van Cauter,et al.  Interconnection between circadian clocks and thyroid function , 2019, Nature Reviews Endocrinology.

[15]  B. Biondi,et al.  Subclinical Hypothyroidism: A Review. , 2019, JAMA.

[16]  T. Hansen,et al.  Reference values for fasting serum concentrations of thyroid-stimulating hormone and thyroid hormones in healthy Danish/North-European white children and adolescents , 2019, Scandinavian journal of clinical and laboratory investigation.

[17]  L. Duntas,et al.  Levothyroxine Replacement Therapy and Overuse: A Timely Diagnostic Approach. , 2018, Thyroid : official journal of the American Thyroid Association.

[18]  N. Schoenmakers,et al.  Congenital hypothyroidism : update and perspectives , 2018 .

[19]  Toshiko Tanaka,et al.  Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation , 2018, Nature Communications.

[20]  Xiu-zhi Guo,et al.  Data mining: Seasonal and temperature fluctuations in thyroid-stimulating hormone. , 2018, Clinical biochemistry.

[21]  Y. Hwangbo,et al.  Relation of Subclinical Hypothyroidism is Associated With Cardiovascular Events and All-Cause Mortality in Adults With High Cardiovascular Risk. , 2018, The American journal of cardiology.

[22]  L. Thienpont,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. , 2018, Thyroid : official journal of the American Thyroid Association.

[23]  T. Visser,et al.  Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study. , 2017, Thyroid : official journal of the American Thyroid Association.

[24]  T. Visser,et al.  Thyroid disease in pregnancy: new insights in diagnosis and clinical management , 2017, Nature Reviews Endocrinology.

[25]  M. Nilsson,et al.  Development of the thyroid gland , 2017, Development.

[26]  Christopher-John L Farrell,et al.  Data mining for age-related TSH reference intervals in adulthood , 2017, Clinical chemistry and laboratory medicine.

[27]  O. Franco,et al.  Thyroid Function Characteristics and Determinants: The Rotterdam Study. , 2016, Thyroid : official journal of the American Thyroid Association.

[28]  T. Kirkwood,et al.  Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study , 2016, The Journal of clinical endocrinology and metabolism.

[29]  S. Benvenga,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. , 2015, Thyroid : official journal of the American Thyroid Association.

[30]  S. Alberti,et al.  Epigenetic inheritance and the missing heritability , 2015, Human Genomics.

[31]  G. Chrousos,et al.  Ontogeny, Anatomy, Metabolism and Physiology of the Thyroid , 2015 .

[32]  H. Pijl,et al.  Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism , 2015, Scientific Reports.

[33]  M. den Heijer,et al.  Thyrotropin versus age relation as an indicator of historical iodine intake. , 2015, Thyroid : official journal of the American Thyroid Association.

[34]  M. Zimmermann,et al.  Iodine deficiency and thyroid disorders. , 2015, The lancet. Diabetes & endocrinology.

[35]  Jie Huang,et al.  Whole-genome sequence-based analysis of thyroid function , 2015, Nature communications.

[36]  Valentin V. Fadeev,et al.  Comments to guidelines for the treatment of hypothyroidism prepared by the American thyroid association task force on thyroid hormone replacement , 2015 .

[37]  Anne R Cappola,et al.  Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. , 2014, Thyroid : official journal of the American Thyroid Association.

[38]  P. Vitti,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. , 2014, European journal of endocrinology.

[39]  O. Soldin,et al.  Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. , 2014, Thyroid : official journal of the American Thyroid Association.

[40]  D. Hazlerigg,et al.  Thyroid Hormone and Seasonal Rhythmicity , 2014, Front. Endocrinol..

[41]  G. Brabant,et al.  2013 ETA Guideline: Management of Subclinical Hypothyroidism , 2013, European Thyroid Journal.

[42]  M. Surks,et al.  The aging thyroid , 2013, Current opinion in endocrinology, diabetes, and obesity.

[43]  W. Wiersinga Smoking and thyroid , 2013, Clinical endocrinology.

[44]  E. Lim,et al.  The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex. , 2013, The Journal of clinical endocrinology and metabolism.

[45]  Sun Wook Cho,et al.  Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status. , 2013, The Journal of clinical endocrinology and metabolism.

[46]  Michael J Murphy,et al.  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). , 2013, The Journal of clinical endocrinology and metabolism.

[47]  Irwin Klein,et al.  Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. , 2012, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[48]  J. Murray,et al.  The heritability of metabolic profiles in newborn twins , 2012, Heredity.

[49]  J. Walsh,et al.  Age‐specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction , 2012, Clinical endocrinology.

[50]  A. Newman,et al.  Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. , 2012, The Journal of clinical endocrinology and metabolism.

[51]  S. Pearce,et al.  Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. , 2012, Archives of internal medicine.

[52]  J. Beilby,et al.  Age-related changes in thyroid function: a longitudinal study of a community-based cohort. , 2012, The Journal of clinical endocrinology and metabolism.

[53]  J. Franklyn,et al.  The relationship between serum TSH and free T4 in older people , 2012, Journal of Clinical Pathology.

[54]  K. Downes,et al.  A mutation in the thyroid hormone receptor alpha gene. , 2012, The New England journal of medicine.

[55]  M. Fraga,et al.  Epigenetics and the environment: emerging patterns and implications , 2012, Nature Reviews Genetics.

[56]  P. Laurberg,et al.  The TSH upper reference limit: where are we at? , 2011, Nature Reviews Endocrinology.

[57]  M. Surks,et al.  An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. , 2011, Thyroid : official journal of the American Thyroid Association.

[58]  J. Houwing-Duistermaat,et al.  Familial longevity is associated with decreased thyroid function. , 2010, The Journal of clinical endocrinology and metabolism.

[59]  J. Franklyn,et al.  Subclinical hypothyroidism and the risk of coronary heart disease and mortality. , 2010, JAMA.

[60]  R. Hoermann,et al.  Complex relationship between free thyroxine and TSH in the regulation of thyroid function. , 2010, European journal of endocrinology.

[61]  M. Surks,et al.  Age- and race-based serum thyrotropin reference limits. , 2010, The Journal of clinical endocrinology and metabolism.

[62]  M. Surks,et al.  Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. , 2009, The Journal of clinical endocrinology and metabolism.

[63]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[64]  K. Adeli,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. , 2009, Clinical biochemistry.

[65]  M. Surks,et al.  Extreme longevity is associated with increased serum thyrotropin. , 2009, The Journal of clinical endocrinology and metabolism.

[66]  吴松华,et al.  The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease:a meta analysis , 2008 .

[67]  M. Falchi,et al.  Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort , 2008, Clinical endocrinology.

[68]  B. Biondi,et al.  The clinical significance of subclinical thyroid dysfunction. , 2008, Endocrine reviews.

[69]  M. Surks,et al.  Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. , 2007, The Journal of clinical endocrinology and metabolism.

[70]  M. Surks,et al.  Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. , 2007, Archives of internal medicine.

[71]  L. Vatten,et al.  Tobacco smoking and thyroid function: a population-based study. , 2007, Archives of internal medicine.

[72]  W. Drake,et al.  The endocrine system and ageing , 2007, The Journal of pathology.

[73]  J. Burgess,et al.  Omega-3 fatty acid status in attention-deficit/hyperactivity disorder. , 2006, Prostaglandins, leukotrienes, and essential fatty acids.

[74]  Yushu Li,et al.  Effect of iodine intake on thyroid diseases in China. , 2006, The New England journal of medicine.

[75]  G. Brabant,et al.  Is there a need to redefine the upper normal limit of TSH? , 2006, European journal of endocrinology.

[76]  L. Wartofsky,et al.  The evidence for a narrower thyrotropin reference range is compelling. , 2005, The Journal of clinical endocrinology and metabolism.

[77]  M. Surks,et al.  The thyrotropin reference range should remain unchanged. , 2005, The Journal of clinical endocrinology and metabolism.

[78]  M. Kempers,et al.  Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism. , 2005, The Journal of clinical endocrinology and metabolism.

[79]  P. Sharp Photoperiodic Regulation of Seasonal Breeding in Birds , 2005, Annals of the New York Academy of Sciences.

[80]  A. D. de Craen,et al.  Thyroid status, disability and cognitive function, and survival in old age. , 2004, JAMA.

[81]  N. Murphy,et al.  Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. , 2004, The Journal of clinical endocrinology and metabolism.

[82]  Fiona L. R. Williams,et al.  Human fetal and cord serum thyroid hormones: developmental trends and interrelationships. , 2004, The Journal of clinical endocrinology and metabolism.

[83]  J. Blangero,et al.  Genetic and environmental influences on thyroid hormone variation in Mexican Americans. , 2004, The Journal of clinical endocrinology and metabolism.

[84]  N. Murphy,et al.  The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life. , 2004, The Journal of clinical endocrinology and metabolism.

[85]  Kirsten Ohm Kyvik,et al.  Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. , 2004, The Journal of clinical endocrinology and metabolism.

[86]  L. Demers,et al.  Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease , 2003, Clinical endocrinology.

[87]  C. Dayan,et al.  Whose normal thyroid function is better—yours or mine? , 2002, The Lancet.

[88]  B. Weintraub,et al.  Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. , 2002, Physiological reviews.

[89]  P. Laurberg,et al.  Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. , 2002, The Journal of clinical endocrinology and metabolism.

[90]  W Harry Hannon,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). , 2002, The Journal of clinical endocrinology and metabolism.

[91]  T. Jørgensen,et al.  Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status. , 2000, European journal of endocrinology.

[92]  P. Beck‐Peccoz,et al.  Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. , 1998, The Journal of clinical endocrinology and metabolism.

[93]  D. Rubello,et al.  Unusual association between a thyrotropin-secreting pituitary adenoma and a papillary thyroid carcinoma. , 1998, Thyroid : official journal of the American Thyroid Association.

[94]  K. Nicolaides,et al.  Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. , 1991, The New England journal of medicine.

[95]  J. Nicoloff,et al.  Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. , 1990, The Journal of clinical endocrinology and metabolism.

[96]  J. D. Vijlder,et al.  Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. , 1989, The New England journal of medicine.

[97]  J. Cavanaugh,et al.  Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. , 1987, The New England journal of medicine.

[98]  C. Hobel,et al.  Thyroid function in the term fetus. , 1969, Pediatrics.

[99]  R. Firth Function , 1955, Yearbook of Anthropology.

[100]  E. Jones Disease , 2020, Palgrave Studies in Economic History.

[101]  M. Weickert,et al.  Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. , 2017, The New England journal of medicine.

[102]  M. Segni Disorders of the Thyroid Gland in Infancy, Childhood and Adolescence. , 2017 .

[103]  A. Sayers,et al.  Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. , 2014, JAMA internal medicine.

[104]  A. Morris,et al.  Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. , 2010, The Journal of clinical endocrinology and metabolism.

[105]  M. Polak,et al.  Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. , 2007, The Journal of clinical endocrinology and metabolism.

[106]  D. Fisher Physiological variations in thyroid hormones: physiological and pathophysiological considerations. , 1996, Clinical chemistry.

[107]  K. Nicolaides,et al.  Fetal thyroid function. , 1993, Fetal diagnosis and therapy.

[108]  B. Nisula,et al.  Radioimmunoassay of human thyrotropin: analytical and clinical developments. , 1984, Critical reviews in clinical laboratory sciences.

[109]  B. M. Allen The results of thyroid removal in the larvae of Rana pipiens , 1918 .