Editorial: Local Control of the Timing of Thyroid Hormone Action in the Developing Human Brain

R. Thomas Zoeller

Biology Department University of Massachusetts Morrill Science Center Amherst, Massachusetts 01003

Address all correspondence and requests for reprints to: Dr. R. Thomas Zoeller, University of Massachusetts, Morrill Science Center, Biology Department, Amherst, Massachusetts 01003. E-mail: tzoeller{at}bio.umass.edu.

Frog metamorphosis has long been a fascinating example of thyroid hormone actions on development (1), and insights gained from studies of frog metamorphosis are helping us understand the role of thyroid hormone in the development of a completely different tissue—the human brain. In frogs such as Xenopus laevis, thyroid hormone controls the dramatic transformation from the larval to the adult form (2, 3), in which many larval tissues are lost (e.g. gills and tail), adult structures formed (e.g. limbs), and other organs are remodeled to support adult functioning. Importantly, frog metamorphosis is characterized by an orderly sequence of events; thus, different tissues undergo thyroid hormone-dependent metamorphic changes at different times and at different rates, all in the face of elevated circulating levels of thyroid hormone. A seminal observation is that local metabolism of thyroid hormone is a major factor controlling the timing of tissue responsiveness to thyroid hormone during frog metamorphosis and thus the sequence of metamorphic events (4). In this issue of the JCEM, Kester et al. (5) describe results of a new study indicating that local metabolism of thyroid hormone in different regions of the developing human brain likely contributes to the timing of thyroid hormone-driven development.

Like frog metamorphosis, development of the mammalian brain is characterized by an orderly sequence of developmental events (6). Moreover, the relative timing of maturational events within the brain is quite similar among mammalian species (7). Recent work in both humans and experimental animals demonstrates that thyroid hormone exerts effects on the developing brain throughout a broad period of fetal and neonatal development (8) and that the developmental events and brain structures affected by thyroid hormone differ as development proceeds. Therefore, it is possible that the human brain uses a strategy for "timing" thyroid hormone sensitivity of different brain regions that is similar to that used by Xenopus. The work by Kester et al. represents a key observation suggesting that this is indeed the case.

Kester et al. (5) report that in several brain regions, especially the cerebral cortex, levels of T3 increase during fetal development and this is correlated with an increase in the activity of type 2 deiodinase (D2), whereas the activity of the type 3 deiodinase (D3) is low to undetectable. D2 controls the conversion of T4 to the hormonally active T3, but D3 controls the conversion of T4 to the hormonally inactive reverse T3. Because T3 levels in the fetal cerebral cortex increased to an extent that could not be accounted for simply on the basis of the age-dependent increase in T4, it indicates that D2 is causing the age-dependent increase in T3 from 14–20 wk (postmenstrual age). Importantly, during this same period, the fetal cerebellum has high levels of D3 and low levels of T3. Finally, at later gestational ages, D3 activity in the cerebellum declines and T3 levels increase.

These data further support the concepts that thyroid hormone plays a role in brain development during the fetal period, that different parts of the brain are differentially sensitive to thyroid hormone at any one time during development, and that the sensitivity to thyroid hormone is controlled, in part, by local control of hormone production. In turn, these observations imply that the consequences of thyroid hormone insufficiency during fetal development will differ from those of thyroid hormone insufficiency during postnatal development. In fact, this implication is supported by empirical evidence. For example, Smit et al. (9) studied a small group of infants of women with hypothyroidism diagnosed before pregnancy who were seemingly adequately treated. Although tests indicated that their children displayed normal neurophysiological and motor development, they had significantly lower mental development indices at 6 and 12 months. Importantly, Rovet et al. (10) followed a relatively large group of infants whose mothers had hypothyroidism diagnosed before or during pregnancy and found mild effects on specific cognitive abilities, particularly visual attention and visuospatial processing abilities. Compared with offspring of euthyroid women, these children showed poorer attention, slower and more variable reaction times to visual stimuli, and visual deficits, particularly reduced contrast sensitivity. Moreover, the specific types of visual deficits appeared to reflect the timing of thyroid hormone insufficiency during pregnancy (11).

The concept that the fetal brain is sensitive to thyroid hormone is of relatively recent origin. Early work indicated that thyroid hormone is not transferred from the mother to the fetus because the human placenta and fetal membranes contain high levels of D3 that degrade thyroid hormones and might prevent such transfer (12, 13). Thus, it was somewhat paradoxical that, in the 1960s and 1970s, Man et al. (14) published the results of a series of studies that found an association between "butenol-extractable iodine" in pregnant women and measures of cognitive function in the offspring, indicating that thyroid hormone may play a role in fetal brain development. This paradox was reconciled in part by Vulsma et al. (15) who reported that newborns with a genetic incapacity to synthesize thyroid hormones have T4 levels that are nearly the same as normal neonates, indicating that the fetus obtains a considerable proportion if its T4 from maternal circulation and this is likely to be true throughout gestation.

The observations of Vulsma et al. were pivotal because the fetus does not begin to produce its own thyroid hormone until around the end of the first trimester (16); therefore, if thyroid hormone acts on the fetal brain in the first trimester, the only source of hormone would be the mother. In fact, thyroid hormones are detected in human coelomic fluid as early as 8 wk gestation (17, 18), several weeks before the onset of thyroid function at 10–12 wk (16), and these levels of thyroid hormones are biologically relevant (19). In addition, all the major thyroid receptor (TR) isoforms are present in human cerebral cortex as early as 8 wk gestation, with immunostaining being reported for TR expression in cerebellar pyramidal cells and Purkinje cells at this time (20, 21). TRs in fetal brain appear to be occupied by thyroid hormone as early as 9 wk gestation (17) and the proportion of TR occupancy by thyroid hormone is in the range known to produce physiological effects.

More recent studies have confirmed that thyroid hormone of maternal origin exerts functional effects on the fetus. Pop et al. (22, 23) showed that levels of free T4, and the presence of circulating antibodies for thyroid peroxidase, were strong predictors of infant mental development and children’s IQ. In addition, these authors found that children of women with hypothyroxinemia at 12 wk gestation had delayed mental and motor function compared with controls; the two groups were different by 8–10 index points on the mental and motor scales at both 1 and 2 yr of age (24). Finally, Haddow and colleagues (25, 26) showed that the children of women with low circulating levels of thyroid hormone exhibit a number of measurable neurological deficits depending on the severity of the hormonal insufficiency. Thus, the literature supports the conclusion that thyroid hormone insufficiency in pregnancy can lead to cognitive deficits in the offspring, clearly indicating that thyroid hormone plays an important role in fetal brain development.

Recent authors discuss the relative merits of developing a routine screening program for thyroid function in pregnant women (27, 28, 29, 30, 31). The relative lack of information about the potential adverse consequences, to the mother or to the fetus, of T4 replacement therapy in pregnant women is one of the critical arguments that screening programs should not presently be implemented, although T4 replacement is recommended for pregnant women who are clinically hypothyroid (29) and an increase in the dose of T4 replacement is recommended for pregnant women currently on T4 replacement (32). Recent animal studies indicate that thyroid hormone insufficiency in the mother can influence cortical neuronal migration in the absence of effects on maternal TSH. Specifically, Ausò et al. (33) found that 3 d of methimazole treatment to pregnant rats could alter neuronal migration in the cerebral cortex without affecting maternal TSH. In combination with the observations of Kester et al. (5), it is important to recognize that, although the deiodinases may account for tissue differences in thyroid hormone sensitivity, they may not always compensate for changes in circulating levels of thyroid hormone.

Footnotes

Abbreviations: D2, Type 2 deiodinase; D3, type 3 deiodinase; TR, thyroid receptor.

Received May 19, 2004.

Accepted May 20, 2004.

References

  1. Shi YB, Wong J, Puzianowska-Kuznicka M, Stolow MA 1996 Tadpole competence and tissue-specific temporal regulation of amphibian metamorphosis: roles of thyroid hormone and its receptors. Bioessays 18:391–399[Medline]
  2. Brown DD, Wang Z, Kanamori A, Eliceiri B, Furlow JD, Schwartzman R 1995 Amphibian metamorphosis: a complex program of gene expression changes controlled by the thyroid hormone. Recent Prog Horm Res 50:309–315[Medline]
  3. Kanamori A, Brown DD 1996 The analysis of complex developmental programmes: amphibian metamorphosis. Genes Cell 1:429–435[Abstract/Free Full Text]
  4. Cai L, Brown DD 2004 Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevis. Dev Biol 266:87–95[CrossRef][Medline]
  5. Kester MHA, Martinez de Mena R, Jesus Obregon M, Marinkovic D, Howatson A, Visser TJ, Hume R, Morreale de Escobar G 2004 Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 89:3117–3128[Abstract/Free Full Text]
  6. Cowan WM, Jessell TM, Zipursky SL, eds 1997 Molecular and cellular approaches to neural development. New York: Oxford University Press
  7. Clancy B, Darlington RB, Finlay BL 2001 Translating developmental time across mammalian species. Neuroscience 105:7–17[CrossRef][Medline]
  8. Chan S, Rovet J 2003 Thyroid hormones in the fetal central nervous system development. Fetal Matern Med Rev 14:177–208[CrossRef]
  9. Smit BJ, Kok JH, Vulsma T, Briet JM, Boer K, Wiersinga WM 2000 Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr 89:291–295[CrossRef][Medline]
  10. Rovet JF, Hepworth SL 2001 Dissociating attention deficits in children with ADHD and congenital hypothyroidism using multiple CPTs. J Child Psychol Psychiatr 42:1049–1056[Medline]
  11. Mirabella G, Feig D, Astzalos E, Perlman K, Rovet JF 2000 The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities. J Pediatr Endocrinol Metab 13:191–194[Medline]
  12. Roti E, Fang S-L, Green K, Emerson CH, Braverman LE 1981 Human placenta is an active site of thyroxine and 3,3'5-triiodothyronine tyrosyl ring deiodination. J Clin Endocrinol Metab 53:498–501[Abstract]
  13. Roti E, Fang S-L, Green K, Braverman LE, Emerson CH 1983 Inner ring deiodination of thyroxine and 3,5,3'-triiodothyronine by human fetal membranes. Am J Obstet Gynecol 147:788–792[Medline]
  14. Man EB, Adelman M, Jones WS, Lord Jr RM 1970 Development and BEI of full-term and low-birth-weight infants through 18 months. Am J Dis Child 119:298–307[Medline]
  15. Vulsma T, Gons MH, de Vijlder JJ 1989 Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321:13–16[Abstract]
  16. Fisher D, Dussault J, Sack J, Chopra I 1977 Ontogenesis of hypothalamic-pituitary-thyroid function and metabolism in man, sheep, rat. Recent Prog Horm Res 33:59–107
  17. Bernal J, Pekonen F 1984 Ontogenesis of the nuclear 3,5,3'-triiodothyronine receptor in the human fetal brain. Endocrinology 114:677–679[Abstract]
  18. Perez-Castillo A, Bernal J, Ferreiro B, Pans T 1985 The early ontogenesis of thyroid hormone receptor in the rat fetus. Endocrinology 117:2457–2461[Abstract]
  19. Calvo RM, 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. J Clin Endocrinol Metab 87:1768–1777[Abstract/Free Full Text]
  20. Kilby MD, Gittoes N, McCabe C, Verhaeg J, Franklyn JA 2000 Expression of thyroid receptor isoforms in the human fetal central nervous system and the effects of intrauterine growth restriction. Clin Endocrinol (Oxf) 53:469–477[CrossRef][Medline]
  21. Chan S, Kilby MD 2000 Thyroid hormone and central nervous system development. J Endocrinol 165:1–8[Free Full Text]
  22. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL 1999 Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149–155[CrossRef][Medline]
  23. Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, Donkers MM, Komproe IH, van Son MM, Vader HL 1995 Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 80:3561–3566[Abstract]
  24. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ 2003 Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 59:282–288[CrossRef][Medline]
  25. 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 1999 Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549–555[Abstract/Free Full Text]
  26. Klein RZ, Sargent JD, Larsen PR, Waisbren SE, Haddow JE, Mitchell ML 2001 Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen 8:18–20[CrossRef][Medline]
  27. Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix JD, Klein RZ 2000 Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 7:127–130[CrossRef][Medline]
  28. Morreale de Escobar G 2001 The role of thyroid hormone in fetal neurodevelopment. J Pediatr Endocrinol Metab 14(Suppl 6):1453–1462
  29. Redmond GP 2002 Hypothyroidism and women’s health. Int J Fertil Womens Med 47:123–127[Medline]
  30. Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G 2003 Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082[Abstract/Free Full Text]
  31. 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 2004 Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228–238[Abstract/Free Full Text]
  32. Brent GA 1999 Maternal hypothyroidism: recognition and management. Thyroid 9:661–665[Medline]
  33. Ausò E, Lavado-Autric R, Cuevas E, Escobar del Rey F, Morreale de Escobar G, Berbel P 15 April 2004 A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 10.1210/en. 2004-0274