TSH concentration within the normal range is associated with cognitive function and ADHD symptoms in healthy preschoolers
Mar Álvarez-Pedrerol,
Núria Ribas-Fitó,
Maties Torrent, Jordi Julvez,
Carlos Ferrer,
Jordi Sunyer,
Mar Álvarez-Pedrerol
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorNúria Ribas-Fitó
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorJordi Julvez
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorCarlos Ferrer
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorJordi Sunyer
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Pompeu Fabra University, Barcelona, Spain
Search for more papers by this authorMar Álvarez-Pedrerol,
Núria Ribas-Fitó,
Maties Torrent, Jordi Julvez,
Carlos Ferrer,
Jordi Sunyer,
Mar Álvarez-Pedrerol
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorNúria Ribas-Fitó
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorJordi Julvez
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorCarlos Ferrer
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Search for more papers by this authorJordi Sunyer
Centre for Research in Environmental Epidemiology – IMIM, Barcelona
Pompeu Fabra University, Barcelona, Spain
Search for more papers by this author Dr Jordi Sunyer, Centre for Research in Environmental Epidemiology – IMIM, C. Doctor Aiguader 88, 08003 Barcelona, Spain. Tel.: +34 93 316 04 00; Fax: +34 93 316 04 10; E-mail: [email protected]
Summary
Objective Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.
Design subjects and measurements Children from two general population birth cohorts in Menorca (n = 289) and Ribera d’Ebre (n = 53), Spain, were assessed in a cross-sectional study at the age of 4. Thyroid hormones (free T4 and T3) and TSH concentrations were measured and mental and motor development was assessed using McCarthy's scales for neuropsychological outcomes and ADHD-DSM-IV for attention deficit and hyperactivity/impulsivity symptoms.
Results Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy's scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 (P < 0·05) and 6·9 (P < 0·01) points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms (odds ratio: 0·25; P < 0·01); these findings were observed in both cohorts despite differences in mean TSH concentrations. No associations were observed with T3.
Conclusions Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.
References
- 1 De Escobar, G.M., Obregon, M.J. & Del Rey, F.E. (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Practice and Research. Clinical Endocrinology and Metabolism, 18, 225–248.
- 2 Chan, S. & Kilby, M.D. (2000) Thyroid hormone and central nervous system development. Journal of Endocrinology, 165, 1–8.
- 3 Porterfield, S.P. & Hendrich, C.E. (1993) The role of thyroid hormones in prenatal and neonatal neurological development – current perspectives. Endocrine Reviews, 14, 94–106.
- 4 Anderson, G.W. (2001) Thyroid hormones and the brain. Frontiers in Neuroendocrinology, 22, 1–17.
- 5 MedlinePlus Medical Encyclopedia. http://www.nlm.nih.gov/medlineplus/ency/article/001193.htm Updated on 20 October 2005 by Nikheel, S., Kolatkar, M.D. Review provided by VeriMed Healthcare Network.
- 6 Haddow, J.E., Palomaki, G.E., Allan, W.C., Williams, J.R., Knight, G.J., Gagnon, J., O’Heir, C.E., Mitchell, M.L., Hermos, R.J., Waisbren, S.E., Faix, J.D. & Klein, R.Z. (1999) Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine, 341, 549–555.
- 7 Pop, V.J., Kuijpens, J.L., Van Baar, A.L., Verkerk, G., Van Son, M.M., De Vijlder, J.J., Vulsma, T., Wiersinga, W.M., Drexhage, H.A. & Vader, H.L. (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clinical Endocrinology, 50, 149–155.
- 8 Calvo, R.M., Jauniaux, E., Gulbis, B., Asuncion, M., Gervy, C., Contempre, B. & Morreale de Escobar, G. (2002) Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. Journal of Clinical Endocrinology and Metabolism, 87, 1768–1777.
- 9 Kooistra, L., Laane, C., Vulsma, T., Schellekens, J.M., Van Der Meere, J.J. & Kalverboer, A.F. (1994) Motor and cognitive development in children with congenital hypothyroidism. Journal of Pediatrics, 124, 903–909.
- 10 Murphy, G.H., Hulse, J.A., Smith, I. & Grant, D.B. (1990) Congenital hypothyroidism: physiological and psychological factors in early development. Journal of Child Psychology and Psychiatry, 31, 711–725.
- 11 Rovet, J.F., Ehrlich, R.M. & Sorbara, D.L. (1992) Neurodevelopment in infants and preschool children with congenital hypothyroidism: etiological and treatment factors affecting outcome. Journal of Pediatric Psychology, 17, 187–213.
- 12 Rovet, J.F. & Ehrlich, R.M. (1995) Long-term effects of 1-thyroxine therapy for congenital hypothyroidism. Journal of Pediatrics, 126, 380–386.
- 13 Rovet, J. (1999) Congenital hypothyroidism: long-term outcome. Thyroid, 9, 741–748.
- 14 Weber, G., Mora, S., Prina Cerai, L.M., Siragusa, V., Colombini, J., Medaglini, S., Fornara, C., Locatelli, T., Comi, G. & Chiumello, G. (2000) Cognitive function and neurophysiological evaluation in early-treated hypothyroid children. Neurological Sciences, 21, 307–314.
- 15 Glorieux, J., Dussault, J.H., Letarte, J., Guyda, H. & Morissette, J. (1983) Preliminary results on the mental development in children with hypothyroidism detected by Quebec Screening Programme. Journal of Pediatrics, 102, 19–22.
- 16 Glorieux, J., Dussault, J.H., Morissette, J., Desjardins, M., Letarte, J. & Guyda, H. (1985) Follow-up at ages 5 and 7 years on mental development in children with hypothyroidism detected by Quebec Programme. Journal of Pediatrics, 107, 913–915.
- 17 Tillotson, S.L., Fuggle, P.W., Smith, I., Ades, A.E. & Grant, D.B. (1994) Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. British Medical Journal, 309, 440–445.
- 18 New England Congenital Hypothyroidism Collaborative. (1981) Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. Lancet, 2, 1095–1098.
- 19 Bauer, M. & Whybrow, P.C. (2001) Thyroid hormone, neural tissue and mood modulation. The World Journal of Biological Psychiatry, 2, 59–69.
- 20 Tejani-Butt, S.M., Yang, J. & Kaviani, A. (1993) Time course of altered thyroid states on 5-HT1A receptors and 5-HT uptake sites in rat brain: an autoradiographic analysis. Neuroendocrinology, 57, 1011–1018.
- 21 Tejani-Butt, S.M. & Yang, J. (1994) A time course of altered thyroid states on the noradrenergic system in rat brain by quantitative autoradiography. Neuroendocrinology, 59, 235–244.
- 22 Constant, E.L., De Volder, A.G., Ivanoiu, A., Bol, A., Labar, D., Seghers, A., Cosnard, G., Melin, J. & Daumerie, C. (2001) Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. Journal of Clinical Endocrinology and Metabolism, 86, 3864–3870.
- 23 Yen, P.M. (2001) Physiological and molecular basis of thyroid hormone action. Physiological Reviews, 81, 1097–1142.
- 24 Madeira, M.D., Sousa, N., Lima-Andrade, M.T., Calheiros, F., Cadete-Leite, A. & Paula-Barbosa, M.M. (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. Journal of Comparative Neurology, 322, 501–518.
- 25 Rami, A., Patel, A.J. & Rabie, A. (1986) Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience, 19, 1217–1226.
- 26 Gould, E., Allan, M.D. & McEwen, B.S. (1990) Dendritic spine density of adult hippocampal pyramidal cells is sensitive to thyroid hormone. Brain Research, 525, 327–329.
- 27 Whybrow, P.C. & Bauer, M. (2005) Behavioral and psychiatric aspects of hypothyroidism. In: L.E. Braverman, R.D. Utiger eds. The Thyroid, 9th edn. Lippincott Williams & Wilkins, Philadelphia, 842–849.
- 28 Whybrow, P.C. & Bauer, M. (2005) Behavioral and psychiatric aspects of thyroxicosis. In: L.E. Braverman, R.D. Utiger eds. The Thyroid, 9th edn. Lippincott Williams & Wilkins, Philadelphia, 644–650.
- 29 Dugbartey, A.T. (1998) Neurocognitive aspects of hypothyroidism. Archives of International Medicine, 158, 1413–1418.
- 30 Polk, S., Sunyer, J., Munoz-Ortiz, L., Barnes, M., Torrent, M., Figueroa, C., Harris, J., Vall, O., Anto, J.M. & Cullinan, P. (2004) A prospective study of Fel d1 and Der p1 exposure in infancy and childhood wheezing. American Journal of Respiratory and Critical Care Medicine, 170, 273–278.
- 31 Ribas-Fito, N., Cardo, E., Sala, M., De Muga, E., Mazon, C., Verdu, A., Kogevinas, M., Grimalt, J.O. & Sunyer, J. (2003) Breastfeeding, exposure to organochlorine compounds, and neurodevelopment in infants. Pediatrics, 111, e580–e585.
- 32 Ribas-Fito, N., Torrent, M., Carrizo, D., Muñoz-Ortiz, L., Julvez, J., Grimalt, J.O. & Sunyer, J. (2006) In utero exposure to background concentrations of DDT and cognitive functioning among preschoolers. American Journal of Epidemiology, 164, 955–962.
- 33 McCarthy, D. (1972) Manual for the McCarthy Scales of Children's Abilities. Psychological Corp, New York.
- 34 American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edn. American Psychiatric Association, Washington, DC.
- 35 Grimalt, J.O., Sunyer, J., Moreno, V., Amaral, O.C., Sala, M., Rosell, A., Anto, J.M. & Albaiges, J. (1994) Risk excess of soft-tissue sarcoma and thyroid cancer in a community exposed to airborne organochlorinated compound mixtures with a high hexachlorobenzene content. International Journal of Cancer, 56, 200–203.
- 36 Sala, M., Sunyer, J., Herrero, C., To-Figueras, J. & Grimalt, J.O. (2001) Association between serum concentrations of hexachlorobenzene and polychlorobiphenyls with thyroid hormone and liver enzymes in a sample of the general population. Occupational Environmental Medicine, 58, 172–177.
- 37 Utiger, R.D. (1999) Editorial: Maternal hypothyroidism and fetal development. New England Journal of Medicine, 341, 601–602.
- 38 Vermiglio, F., Lo Presti, V.P., Moleti, M., Sidoti, M., Tortorella, G., Scaffidi, G., Castagna, M.G., Mattina, F., Violi, M.A., Crisa, A., Artemisia, A. & Trimarchi, F. (2004) Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. Journal of Clinical Endocrinology and Metabolism, 89, 6054–6060.
- 39 Stein, M.A., Weiss, R.E. & Refetoff, S. (1995) Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder. Journal of Developmental and Behavioral Pediatrics, 16, 406–411.
- 40 Ganguli, M., Burmeister, L.A., Seaberg, E.C., Belle, S. & DeKosky, S.T. (1996) Association between dementia and elevated TSH: a community-based study. Biological Psychiatry, 40, 714–725.
- 41 Stein, M.A. & Weiss, R.E. (2003) Thyroid function tests and neurocognitive functioning in children referred for attention deficit/hyperactivity disorder. Psychoneuroendocrinology, 28, 304–316.
- 42 Weiss, R.E., Stein, M.A., Trommer, B. & Refetoff, S. (1993) Attention-deficit hyperactivity disorder and thyroid function. The Journal of Pediatrics, 123, 539–545.
- 43 Dorn, L.D. (1997) Baseline thyroid hormones in depressed and non-depressed pre- and early-pubertal boys and girls. Journal of Psychiatric Research, 31, 555–567.
- 44 Wahlin, A., Wahlin, T.B., Small, B.J. & Backman, L. (1998) Influences of thyroid stimulating hormone on cognitive functioning in very old age. The Journals of Gerontology: Psychological Sciences and Social Sciences, 53, 234–239.
- 45 Wahlin, A., Bunce, D. & Wahlin, T.B. (2005) Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age. Psychoneuroendocrinology, 30, 625–637.
- 46 Andersen, S., Pedersen, K.M., Bruun, N.H. & Laurberg, P. (2002) Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. Journal of Clinical Endocrinology and Metabolism, 87, 1068–1072.
- 47 Demers, L.M. & Spencer, C.A. (2002) Laboratory Medicine Practice Guidelines. Laboratory support for the Diagnosis and Monitoring of Thyroid Disease, National Academy of Clinical Biochemistry (NACB). Available at: http://www.nacb.org/lmpg/thyroid_LMPG_Word.stm (accessed 25 May 2006).
- 48 Meier, C.A., Maisey, M.N., Lowry, A., Muller, J. & Smith, M.A. (1993) Interindividual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests. Clinical Endocrinology, 39, 101–107.
- 49 Elmlinger, M.W., Kuhnel, W., Lambrecht, H.G. & Ranke, M.B. (2001) Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH). Clinical Chemistry and Laboratory Medicine, 39, 973–979.
- 50 Surks, M.I., Ortiz, E., Daniels, G.H., Sawin, C.T., Col, N.F., Cobin, R.H., Franklyn, J.A., Hershman, J.M., Burman, K.D., Denke, M.A., Gorman, C., Cooper, R.S. & Weissman, N.J. (2004) Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA, 291, 228–238.
- 51 Baldini, I.M., Vita, A., Mauri, M.C., Amodei, V., Carrisi, M., Bravin, S. & Cantalamessa, L. (1997) Psychopathological and cognitive features in subclinical hypothyroidism. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 21, 925–935.
- 52 McDermott, M.T. & Ridgway, E.C. (2001) Subclinical hypothyroidism is mild thyroid failure and should be treated. Journal of Clinical Endocrinology and Metabolism, 86, 4585–4590.
- 53 Razvi, S., Ingoe, L., Keeka, G., Oates, C., McMillan, C. & Weaverm, J.U. (2007) The beneficial effect of 1-thyroxine on cardiovascular risk factors, endothelial function and quality of life in subclinical hypothyroidism: randomised, crossover trial. Journal of Clinical Endocrinology and Metabolism, in press.
- 54 British Thyroid Association. (2006) UK Guidelines for Thyroid Function Tests, July. Available at: http://www.british-thyroid-association.org/TFT_guideline_final_version_July_2006.pdf (accessed 24 July 2006).
Citing Literature
