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Thyroid hormone replacement therapy in the perinatal period: Neurologic considerations
EDITOR'S COLUMN
Thyroid hormone replacement therapy in the perinatal period." Neurologic considerations
THE ESTABLISHMENT of pilot screening programs for congenital hypothyroidism in five geographic areas of North America has resulted in the detection of 72 affected infants through September, 1976--an incidence of one in 5,900 live births? Although studies continue of possible approaches to intrauterine diagnosis, 2 preliminary investigations of methods for potential intrauterine fetal thyroid hormone replacement therapy are in progress? ,* It is likely, therefore, that thyroid replacement therapy will be instituted in the human newborn infant with increasing frequency: Both human and animal placentas are essentially impermeable to thyroid hormones. Nevertheless, the hypothyroid human newborn infant appears euthyroid, suggesting that fetal growth and development are not dependent on thyroid hormone.'-' As in the case of perinatal glucocorticoid therapy? perinatal thyroid treatment may have both acute and latent effects on brain development. The human infant brain clearly has a critical period of thyroid hormone-dependent development, ~'~ but the extent to which brain development depends on thyroid hormones in utero is not clear. The critical period occurs postnatally in the rat, 9 but m a y extend into the intrauterine p e r i o d in man and other species in which the central nervous system is more mature at birth. In the sheep, whose offspring has a brain more mature at birth than that in the human being, thyroid hormone deficiency during the last trimester of intrauterine developmentresults in some delay in myelination of the central nervous system? 6 Recent studies of replacement therapy for hypothyroidism suggest that the optimal dose of thyroxine is significantly less than that recommended in the past x' ~'-' in children above age one year; there is little documented experience in the neonatal period. In addition, few followup data exist concerning the possible complications of excessive thyroid hormone on human nervous system Supported by National Institute o f Health Grant H D 09277-03, from the United States Public Health Service.
0022-3476/78/0692-1'035500.40/0 9 1978 The C, V. Mosby Co.
development. Both neonatal hyperthyroidism 1~and excessive thyroid hormone replacement therapy for congenital hypothyroidism ~4 have b e e n associated with premature craniosynostosis, at times accompanied by increased intraCranial pressure and delayed neurologic development. aa See related articles, pp. 963, 969, and 974.
Abbreviations used T~: tri-iodothyronine TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone T~: thyroxine The growth spurt of the human brain occurs postnatally.1~ Dobbing and Sands 1~ have shown that a surge of DNA acquisition at 10 to 18 weeks' gestation represents neuronal proliferation and is followed by another surge that begins in the third trimester and represents proliferation of glial cells. A prolonged period of myelination follows, lasting several years. In the human cerebellum, division and migration of granule cell precursors occur in the external granular layer throughout the first year of life. 16 Substantial neuronal division occurs postnatally in the hippocampus of both mouse 17 and rat 16-2~ whose growth spurt occurs postnatally, as well as the guinea pig ~1 whose brain at birth is considerably more mature than that of the human infant. These findings suggest that cell division and myelination in the human hippocampus, as well as in the cerebrum and cerebellum, may be particularly vulnerable during the thyroid-dependent period of postnatal brain development of the human infant. IMMEDIATE EFFECTS OF NEONATAL THYROTOXICOSIS IN ANIMALS Most information regarding the immediate and longterm complications of excessive thyroid hormone with respect to brain development must be derived from animal experimentation. A number of recent studies have confirmed a relationship between excessive thyroid The Journal o f P E D 1 A T R I C S Vol. 92. No. O, pp. 1035-1038
1035
1 036
Editor's column
hormones and accumulation of D N A in the developing rat cerebellum. Bal~izs et alJ 2 using tri-iodothyronine treatment from birth, found a 20 to 30% decrease in brain DNA content, which began during the first extrauterine week in the cerebrum and during the second week in the cerebellum. Using pharmacologic doses of thyroxine m similar experiments. Gourdon et aF ~ noted a significant decrease in rat cerebellar D N A content after age 12 days. Nicholson and Altman. 24 using autoradiography, confirmed that experimental hyperthyroidism results in early termination of cell proliferation in the cerebellar external granular layer, as well as early cell differentiation in the molecular and internal granular layers, associated ultimately with decreases in cerebellar granule cells, basket cells, and astrocytes. These investigators9 also demonstrated an initial acceleration in synaptogenesis with ultimate reduction in synapses in the cerebellar molecular layer. In our laboratory, using daily doses of thyroxine from birth in the newborn rat. we noted an acceleration of cerebellar D N A synthesis from days 2 through 6. followed by a subsequent decline to subnormal values for cerebellar DNA content. -~ The activity of thymidine kinase. an enzyme important for D N A synthesis, was induced prematurely in cerebella of treated animals by age one day ~ arid subsequently fell below control values three days before the premature decline in DNA: thus, there was a shift to an earlier age in the developmental spectrum of thymidine kinase activity even prior to the premature acceleration of DNA synthesis. Subsequently, we have shown that other enzymes relating to biosynthesis of pyrimidines and nucleic acids in rat cerebellum are affected by experimental hyperthyroidism ~-2" in a manner somewhat reciprocal to the patterns noted in experimental hypothyroidism. 29-3~These findings support the concept of Hamburgh et al :~ that thyroxine may act as a time clock during the critical period of brain development, controlling the timing of onset and termination of both cellular proliferation and differentiation in the brainY-' In studies involving rat cerebral development, Pelton and Bass ~ have shown that thyroxine administered in excess to normal Or hypothyroid rat pups during early postnatal life disrupts the normal sequence of glial cell mitosis, migration, and differentiation, and results in severe impairment of myelinogenesis of cerebral cortex. The results suggested that excess thyroid hormone suppresses mitotic activity in the subependymal zone, thereby delaying normal glial cell migratio n into cortex and subsequent failure of oligodendroglia to form myelin. This was shown by a marked reduction at 30 postnatal
The Journal of Pediatrics June 1978
days in total cerebral lipid, cholesterol, cerebrosides, and proteolipid proteins, and resulted, in turn, in a reduction in adult concentrations of myelin membrane components to 10 to 30% of normal values. Animals undergoing replacement therapy Often appeared clinically thyrotoxic in spite of failure tO correct the nervous system abnormalities of hypothyroidism. It was concluded that the failure of hormonal replacement therapy in the cretin rat, when delivered in amounts exceeding physiologic requirements, can be ascribed,not merely to the delay in the o n s e t o f treatment; but to a direct toxic effect o f the hormone on the developing brain. LATENT EFFECTS OF PERINATAL HYPERTHYROIDISM Injection of pharmacologic doses of thyroxine into rats during the first 5 days of life has been shown to produce a variety of endocrine alterations that persist throughout adult life,34 including a delay in puberty and reduced fertility, as well as reduced Ovarian, testicular, adrenal, and ventral prostate weights. Such neonatal thyrotoxicosis also results in a persistent alteration in hypothalamic control of thyroid function with an abnormal sensitivity to feedback regulation of thyroid-stimulating hormone synthesis and secretion by circulating thyroid hormones? 4 The abnormality is similar to that seen in rats with specific hypothalamic lesions. 35 Although content of hypothalamic thyrotropin-releasing hormone is increased during adulthood in these animals, :~6 the circulating concentration of TRH was found to be decreased, 34 supporting the theory that the observed long-term effects may be the result of impaired hypothalamic secretion of TRH. In studies involving corticosteroid regulation, Meserve and Leathern ~7 noted that neonatal hyperthyroidism accelerated maturation of the hypothalamo-hypophysialadrenal axis, whereas neonatal hypothyroidism prolonged the stress nonresponsive period. Hyperthyroid pups produced by feeding mothers dessicated thyroid throughout gestation and the early neonatal period were noted to respond to stress and exogenous ACTH at age 12 days with both synthesis and release of cortieosterone, whereas euthyroid pups responded only by corticosterone synthesis. Observations from our laboratory suggest that daily administration Of thyroxine greatly accelerates the maturation of the corticosterone response to handling stress in neonatal rats 38 without altering the onset of corticosterone circadian rhythms. (Poland R, and Weichsel ME Jr, unpublished data). Accelerated maturation of the electroencephalogram and startle reflexes in rats treated neonatally with thyroxine has been shown by Schapiro ~9 to correlate with
Volume 92 Number 6
an accelerated learning ability in the young rat. This early behavioral acceleration was felt by Davenport and Gonzales 4~ and by Stone and Greenough ~1 to be due to differences in locomotor activity rather than learning. Importantly, this initial advantage in integrating environmental information in thyroxine-treated rat pups was associated with a relative decrease in such ability at a later stage of development. 3~-4~ It was felt by Schapiro a9 that excess thyroxine administered during the early postnatal period of development may compromise the capability o f certain adaptive or survival value mechanisms at later stages of the life cycle: In an important clinical study of congenitally hypothyroid children treated after age two years with varying doses of thyroxine, Sato et al ~3 have recently demonstrated an alteration in the pituitary threshhold for TSH secretion. This study established for the first time, the existence of a clinical counterpart to the animal studies of Bakke et al:". 44 describing latent effects of neonatal thyroid insufficiency or excess on ultimate sensitivity to feedback regulation of the hypothalamo-pituitary-thyroid axis. CONCLUSIONS Normally, in the h u m a n fetus, there is a rapid maturation of hypothalamic-pituitary control of thyroid function between 20 and 30 weeks' gestation? 5 D u r i n g this time fetal serum TSH concentratioris increase two- to threefold and total serum thyroxine concentrations increase from less than 4/xg/dl before 20 weeks to a m e a n level of 9.4 t~g/dl at 30 weeks. Thus, in premature infants under 30 to 32 weeks' gestation, there is a period of physiologic hypothyroidism that may lead to an inability to discern a normal physiologic state f r o m significant congenital hypothyroidism. Moreover, this period of h y p o t h a l a m i c maturation in the h u m a n being resembles that in the rat during the first 10 to 14 days of extrauterine life; as in the rat, normal hypothalamic maturation may be dependent on a narrow range of "normal" thyroid hormone levels. The recent observation of significantly lowered T4 and T~ values in premature infants with the respiratory distress syndrome ~5. ~ has led to the administration of T~ or T~ to several such premature infantsW Thus the expected increase in the use of thyroid hormone replacement therapy for congenital hypothyroidism detected in the newborn infant at term by mass screening programs may be further augmented by attempts to treat metabolic and functional alterations associated with evidence of thyroid dysfunction during prematurity in normal and disease states. In such efforts it is important to consider the possible harmful effects of overtreatment as well as
Editor's column
10 3 7
undertreatment, and to titrate carefully the exogenous hormone to provide "normal" blood levels of thyroxine and tri-iodothyronine. The author is grateful to Dr. Delbert A. Fisher for advice and critical review ofthe manuscript. Morton E. Weichsel, Jr., M.D. Departments o f Pediatrics and Neurology Perinatal Research Laboratories Harbor General Hospital Campus UCLA School of Medicine Torrance, CA 90509 REFERENCES
1. Scriver CRI Feingold M, Mamunes P, and Nadler HL: Screening for congenital metabolic disorders in the newborn infant: Congenital deficiency of thyroid hormone and hyperphenylalaninemia, Pediatrics (Suppl) 60:389, 1977. 2. Fisher DA: Neonatal detection of hypothyroidism, J PEDIATR 86:822, 1975. 3. Hobel CJ, Sack J, Cousins LM, and Fisher DA: The effect of intraamniotic thyroxine on thyroid function in the human fetus and newborn, Clin Res 25:198a, 1977. 4. Sack J, and Fisher DA: Thyroid hormone metabolism in amni0tic fluid of man and sheep, in DA Fisher, and GN Burrow, editors: Perinatal thyroid physiology and disease, New York, !975, Raven Press; pp 49-58. 5. Weichsel ME Jr: The therapeutic use of glucocorticoids in the perinatal period: Potential neurological hazards, Ann Neurol 2:364, 1977. 6. Klein A, Meltzer S, and Kenny F: Improved prognosis in congenital hypothyroidism treated before age three months, J PEDIATR81:912, 1972. 7. Raiti S, and Newns GH: Cretinism: Early diagnosis and its relation to mental prognosis, Arch Dis Child 46:692, 1971. 8. Smith DW, Blizzard RM, and Wilkins L: The mental prognosis in hypothyroidism of infancy and childhood: A review of 128 cases, Pediatrics 18:1011, 1957. 9. Nicholson JL, and Altman J: Synaptogenesis in the rat cerebellum: Effects of early hypo- and hyperthyroidism, Science 176:530, 1972. 10. Erenberg A, Omori K, Menkes JH, Oh W, and Fisher DA: Growth and development of the thyroidectomized ovine fetus, Pediatr Res 8:783, 1974. 11. Rezvani I, and DiGeorge AM: Reassessment of the daily dose of oral thyroxine for replacement therapy in hypothyroid children, J PEDIATR90:291, 1977i 12. Abbassi V, and Aldige C: Evaluation of sodium L-thyroxine (T4) requirement in replacement therapy of hypothyroidism, J PEDIATR90:298, 1977. 13. Riggs W Jr, Wilroy SR, and Etteldorf JN: Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis, and brachydactyly, Radiology 105:621, 1972. 14. Penfold JL, and Simpson DA: Premature craniosynostosis-a complication of thyroid replacement therapy, J PEDIATR 86:360, 1975.
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Editor's column
15. Dobbing J, and Sands J: Quantitative growth and development of human brain, Arch Dis Child 48:757, 1973. 16. RaafJ, and Kernohan JW: A study of the external granular layer in the cerebellum. The disappearance of the external granular layer and the growth of the molecular and internal granular layers in the cerebellum, Am J Anat 75:151, 1944. 17. Angevine JB Jr: Time of neuron origin in the hippocampal region, Exp Neurol, Suppl 2:1, 1965. 18. Altman J: Autoradiographic and histological studies of postnatal neurogenesis. II. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in infant rats, with special reference to postnatal neurogenesis in some brain regions, J Comp Neurol 128:431, 1968. 19. Bayer SA, and Altman J: Hippocampal development in the rat: Cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation, J Comp Neurol 158:55, 1974. 20. Schlessinger AR, Cowan WM, and Gottlieb DI: An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat, J Comp Neurol 159:149, 1975. 21. Altman J, and Das GD: Postnatal neurogenesis in the guinea-pig, Nature 214:1098, 1967. 22. Balfizs R, Kovacs S, Cocks WA, Johnson AL, and Eayrs JT: Effect of thyroid hormone on the biochemical maturation of rat brain: Postnatal cell formation, Brain Res 25:555, 1971. 23. Gourdon J, Clos J, Coste C, Dainat J, and Legrand J: Comparative effects of hypothyroidism, hyperthyroidism and undernutrition on the protein and nucleic acid contents of the cerebellum in the young rat, J Neurochem 21:861, 1973. 24. Nicholson JL, and Altman J: The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. 1. Cel ! proliferation and differentiation, Brain Res 44:13, 1972. 25. Weichs~l ME Jr: Effect of thyroxine on DNA synthesis and thymidine kinase activity during cerebellar development, Brain Res 78:455, 1974. 26. Clark BR, and Weichsel ME Jr: Correlation of DNA accumulation rate with thymidylate synthetase and thymidine kinase activities in developing rat cerebellum: Effect of thyroxine, J Neurochem 29:91, 1977. 27. Weichsel ME Jr: Thyroxine effect upon activity of uridine kinase in developing rat cerebellum, Biol Neonate 31:199, 1977. 28. Weichsel ME Jr: Effect of thyroxine on de novo pyrimidine biosynthesis in developing rat cerebellum, Brain Res 117:346, 1976. 29. Weichsel ME Jr, and Dawson L: Effects of hypothyroidism and undernutrition upon DNA biosynthesis and thymidine kinase activity during cerebellar development in the rat, J Neurochem 26:675, 1976. 30. Weichsel ME Jr, Clark BR, and Poland RE: Experimental hypothyroidism: relationship between cerebellar cell division and enzymes involving nucleic acid metabolism during development, Pediatr Res 11:250a, 1977.
The Journal of Pediatrics June 1978
31. Weichsel ME Jr, Clark BR, and Poland RE: Effect of hypothyroidism on aspartate transcarbamylase, uridine kinase, and DNA biosynthesis during cerebellar development in the rat, Biol Neonate 32:5, 1977. 32. Hamburgh M, Mendoza LA, Burkart JF, and Weil F: The thyroid as a time clock in the developing nervous system, in Pease DC, editor: Cellular aspects of neural growth and differentiation, UCLA Forum Medical Science, Los Angeles, 1971, University of California Press, pp 321. 33. Pelton EW, and Bass NH: Adverse effects of excess thyroid hormone on the maturation of the rat cerebrum, Arch Neurol 29:145, 1973. 34. Bakke JL, Lawrence NL, Bennett J, and Robinson S: The late effects of neonatal hyperthyroidism upon the feedback regulation of TSH secretion in rats, Endocrinology 97:659, 1975. 35. Martin JB, Boshans R, and Reichlin S: Feedback regulation of TSH secretion in rats with hypothalamic lesions, Endocrinology 87:1032, 1970. 36. Bakke JL, Lawrence N, and Wilber JF: The late effects of neonatal hyperthyroidism upon the hypothalamic-pituitarythyroid axis in the rat, Endocrinology 96:406, 1974. 37. Meserve LA, and Leathern JH: Neonatal hyperthyroidism and maturation of the rat hypothalamo-hypophysealadrenal axis, Proc Soc Exp Biol Med 147:510, 1974. 38. Weichsel ME Jr, and Poland RE: Brain development in perinatal endocrinopathies: Effect of thyroxine on serum glucocorticoid levels, Ann Neurol 2:254a, 1977. 39. Schapiro S: Some physiological, biochemical, and behavioral consequences of neonatal hormone administration: Cortisol and thyroxine, Gen Comp Endocrinol 10:214, 1968. 40. Davenport JW, and Gonzales LM: Neonatal thyroxine stimulation in rats: Accelerated behavioral maturation and subsequent learning deficit, J Comp Physiol 85:397, 1973. 41. Stone JM, and Greenough WT: Excess neonatal thyroxine: Effects on learning in infant and adolescent rats, Dev Psychobiol 8:479, 1975. 42. Eayrs JT: Effect of neonatal hyperthyroidism on maturation and learning in the rat, Anim Behav 12:195, 1964. 43. Sato T, Suzuki Y, Taketarii T, Tshiguro K, and Nakajima H: Age-related change in pituitary threshhold for TSH release during thyroxine replacement therapy for cretinism, J Clin Endocrinol Metab 44:553, 1977. 44. Bakke JL, Lawrence NL, Bennett J, and Robinson S: Endocrine syndromes produced by neonatal hyperthyroidism, hypothyroidism or altered nutrition, and effects seen in untreated progeny, in Fisher DA, and Burrow GN, editors: Perinatal thyroid physiology and disease, Kroc Foundation Symposia Series Vol 3, 1975, p 79. 45. Fisher DA: Thyroid function in the premature infant, Am J Dis Child 131:842, 1977. 46. Cuestas RA, Lindall A, and Engel RR: Low thyroid hormones and respiratory-distress syndrome of the newborn, N E n g l J Med 295:297, 1976. 47. Cuestas RA, and Engel RR: Low thyroid activity in prematures with RDS, Pediatr Res 11:424a, 1977.
Thyroid hormone replacement therapy in the perinatal period." Neurologic considerations
THE ESTABLISHMENT of pilot screening programs for congenital hypothyroidism in five geographic areas of North America has resulted in the detection of 72 affected infants through September, 1976--an incidence of one in 5,900 live births? Although studies continue of possible approaches to intrauterine diagnosis, 2 preliminary investigations of methods for potential intrauterine fetal thyroid hormone replacement therapy are in progress? ,* It is likely, therefore, that thyroid replacement therapy will be instituted in the human newborn infant with increasing frequency: Both human and animal placentas are essentially impermeable to thyroid hormones. Nevertheless, the hypothyroid human newborn infant appears euthyroid, suggesting that fetal growth and development are not dependent on thyroid hormone.'-' As in the case of perinatal glucocorticoid therapy? perinatal thyroid treatment may have both acute and latent effects on brain development. The human infant brain clearly has a critical period of thyroid hormone-dependent development, ~'~ but the extent to which brain development depends on thyroid hormones in utero is not clear. The critical period occurs postnatally in the rat, 9 but m a y extend into the intrauterine p e r i o d in man and other species in which the central nervous system is more mature at birth. In the sheep, whose offspring has a brain more mature at birth than that in the human being, thyroid hormone deficiency during the last trimester of intrauterine developmentresults in some delay in myelination of the central nervous system? 6 Recent studies of replacement therapy for hypothyroidism suggest that the optimal dose of thyroxine is significantly less than that recommended in the past x' ~'-' in children above age one year; there is little documented experience in the neonatal period. In addition, few followup data exist concerning the possible complications of excessive thyroid hormone on human nervous system Supported by National Institute o f Health Grant H D 09277-03, from the United States Public Health Service.
0022-3476/78/0692-1'035500.40/0 9 1978 The C, V. Mosby Co.
development. Both neonatal hyperthyroidism 1~and excessive thyroid hormone replacement therapy for congenital hypothyroidism ~4 have b e e n associated with premature craniosynostosis, at times accompanied by increased intraCranial pressure and delayed neurologic development. aa See related articles, pp. 963, 969, and 974.
Abbreviations used T~: tri-iodothyronine TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone T~: thyroxine The growth spurt of the human brain occurs postnatally.1~ Dobbing and Sands 1~ have shown that a surge of DNA acquisition at 10 to 18 weeks' gestation represents neuronal proliferation and is followed by another surge that begins in the third trimester and represents proliferation of glial cells. A prolonged period of myelination follows, lasting several years. In the human cerebellum, division and migration of granule cell precursors occur in the external granular layer throughout the first year of life. 16 Substantial neuronal division occurs postnatally in the hippocampus of both mouse 17 and rat 16-2~ whose growth spurt occurs postnatally, as well as the guinea pig ~1 whose brain at birth is considerably more mature than that of the human infant. These findings suggest that cell division and myelination in the human hippocampus, as well as in the cerebrum and cerebellum, may be particularly vulnerable during the thyroid-dependent period of postnatal brain development of the human infant. IMMEDIATE EFFECTS OF NEONATAL THYROTOXICOSIS IN ANIMALS Most information regarding the immediate and longterm complications of excessive thyroid hormone with respect to brain development must be derived from animal experimentation. A number of recent studies have confirmed a relationship between excessive thyroid The Journal o f P E D 1 A T R I C S Vol. 92. No. O, pp. 1035-1038
1035
1 036
Editor's column
hormones and accumulation of D N A in the developing rat cerebellum. Bal~izs et alJ 2 using tri-iodothyronine treatment from birth, found a 20 to 30% decrease in brain DNA content, which began during the first extrauterine week in the cerebrum and during the second week in the cerebellum. Using pharmacologic doses of thyroxine m similar experiments. Gourdon et aF ~ noted a significant decrease in rat cerebellar D N A content after age 12 days. Nicholson and Altman. 24 using autoradiography, confirmed that experimental hyperthyroidism results in early termination of cell proliferation in the cerebellar external granular layer, as well as early cell differentiation in the molecular and internal granular layers, associated ultimately with decreases in cerebellar granule cells, basket cells, and astrocytes. These investigators9 also demonstrated an initial acceleration in synaptogenesis with ultimate reduction in synapses in the cerebellar molecular layer. In our laboratory, using daily doses of thyroxine from birth in the newborn rat. we noted an acceleration of cerebellar D N A synthesis from days 2 through 6. followed by a subsequent decline to subnormal values for cerebellar DNA content. -~ The activity of thymidine kinase. an enzyme important for D N A synthesis, was induced prematurely in cerebella of treated animals by age one day ~ arid subsequently fell below control values three days before the premature decline in DNA: thus, there was a shift to an earlier age in the developmental spectrum of thymidine kinase activity even prior to the premature acceleration of DNA synthesis. Subsequently, we have shown that other enzymes relating to biosynthesis of pyrimidines and nucleic acids in rat cerebellum are affected by experimental hyperthyroidism ~-2" in a manner somewhat reciprocal to the patterns noted in experimental hypothyroidism. 29-3~These findings support the concept of Hamburgh et al :~ that thyroxine may act as a time clock during the critical period of brain development, controlling the timing of onset and termination of both cellular proliferation and differentiation in the brainY-' In studies involving rat cerebral development, Pelton and Bass ~ have shown that thyroxine administered in excess to normal Or hypothyroid rat pups during early postnatal life disrupts the normal sequence of glial cell mitosis, migration, and differentiation, and results in severe impairment of myelinogenesis of cerebral cortex. The results suggested that excess thyroid hormone suppresses mitotic activity in the subependymal zone, thereby delaying normal glial cell migratio n into cortex and subsequent failure of oligodendroglia to form myelin. This was shown by a marked reduction at 30 postnatal
The Journal of Pediatrics June 1978
days in total cerebral lipid, cholesterol, cerebrosides, and proteolipid proteins, and resulted, in turn, in a reduction in adult concentrations of myelin membrane components to 10 to 30% of normal values. Animals undergoing replacement therapy Often appeared clinically thyrotoxic in spite of failure tO correct the nervous system abnormalities of hypothyroidism. It was concluded that the failure of hormonal replacement therapy in the cretin rat, when delivered in amounts exceeding physiologic requirements, can be ascribed,not merely to the delay in the o n s e t o f treatment; but to a direct toxic effect o f the hormone on the developing brain. LATENT EFFECTS OF PERINATAL HYPERTHYROIDISM Injection of pharmacologic doses of thyroxine into rats during the first 5 days of life has been shown to produce a variety of endocrine alterations that persist throughout adult life,34 including a delay in puberty and reduced fertility, as well as reduced Ovarian, testicular, adrenal, and ventral prostate weights. Such neonatal thyrotoxicosis also results in a persistent alteration in hypothalamic control of thyroid function with an abnormal sensitivity to feedback regulation of thyroid-stimulating hormone synthesis and secretion by circulating thyroid hormones? 4 The abnormality is similar to that seen in rats with specific hypothalamic lesions. 35 Although content of hypothalamic thyrotropin-releasing hormone is increased during adulthood in these animals, :~6 the circulating concentration of TRH was found to be decreased, 34 supporting the theory that the observed long-term effects may be the result of impaired hypothalamic secretion of TRH. In studies involving corticosteroid regulation, Meserve and Leathern ~7 noted that neonatal hyperthyroidism accelerated maturation of the hypothalamo-hypophysialadrenal axis, whereas neonatal hypothyroidism prolonged the stress nonresponsive period. Hyperthyroid pups produced by feeding mothers dessicated thyroid throughout gestation and the early neonatal period were noted to respond to stress and exogenous ACTH at age 12 days with both synthesis and release of cortieosterone, whereas euthyroid pups responded only by corticosterone synthesis. Observations from our laboratory suggest that daily administration Of thyroxine greatly accelerates the maturation of the corticosterone response to handling stress in neonatal rats 38 without altering the onset of corticosterone circadian rhythms. (Poland R, and Weichsel ME Jr, unpublished data). Accelerated maturation of the electroencephalogram and startle reflexes in rats treated neonatally with thyroxine has been shown by Schapiro ~9 to correlate with
Volume 92 Number 6
an accelerated learning ability in the young rat. This early behavioral acceleration was felt by Davenport and Gonzales 4~ and by Stone and Greenough ~1 to be due to differences in locomotor activity rather than learning. Importantly, this initial advantage in integrating environmental information in thyroxine-treated rat pups was associated with a relative decrease in such ability at a later stage of development. 3~-4~ It was felt by Schapiro a9 that excess thyroxine administered during the early postnatal period of development may compromise the capability o f certain adaptive or survival value mechanisms at later stages of the life cycle: In an important clinical study of congenitally hypothyroid children treated after age two years with varying doses of thyroxine, Sato et al ~3 have recently demonstrated an alteration in the pituitary threshhold for TSH secretion. This study established for the first time, the existence of a clinical counterpart to the animal studies of Bakke et al:". 44 describing latent effects of neonatal thyroid insufficiency or excess on ultimate sensitivity to feedback regulation of the hypothalamo-pituitary-thyroid axis. CONCLUSIONS Normally, in the h u m a n fetus, there is a rapid maturation of hypothalamic-pituitary control of thyroid function between 20 and 30 weeks' gestation? 5 D u r i n g this time fetal serum TSH concentratioris increase two- to threefold and total serum thyroxine concentrations increase from less than 4/xg/dl before 20 weeks to a m e a n level of 9.4 t~g/dl at 30 weeks. Thus, in premature infants under 30 to 32 weeks' gestation, there is a period of physiologic hypothyroidism that may lead to an inability to discern a normal physiologic state f r o m significant congenital hypothyroidism. Moreover, this period of h y p o t h a l a m i c maturation in the h u m a n being resembles that in the rat during the first 10 to 14 days of extrauterine life; as in the rat, normal hypothalamic maturation may be dependent on a narrow range of "normal" thyroid hormone levels. The recent observation of significantly lowered T4 and T~ values in premature infants with the respiratory distress syndrome ~5. ~ has led to the administration of T~ or T~ to several such premature infantsW Thus the expected increase in the use of thyroid hormone replacement therapy for congenital hypothyroidism detected in the newborn infant at term by mass screening programs may be further augmented by attempts to treat metabolic and functional alterations associated with evidence of thyroid dysfunction during prematurity in normal and disease states. In such efforts it is important to consider the possible harmful effects of overtreatment as well as
Editor's column
10 3 7
undertreatment, and to titrate carefully the exogenous hormone to provide "normal" blood levels of thyroxine and tri-iodothyronine. The author is grateful to Dr. Delbert A. Fisher for advice and critical review ofthe manuscript. Morton E. Weichsel, Jr., M.D. Departments o f Pediatrics and Neurology Perinatal Research Laboratories Harbor General Hospital Campus UCLA School of Medicine Torrance, CA 90509 REFERENCES
1. Scriver CRI Feingold M, Mamunes P, and Nadler HL: Screening for congenital metabolic disorders in the newborn infant: Congenital deficiency of thyroid hormone and hyperphenylalaninemia, Pediatrics (Suppl) 60:389, 1977. 2. Fisher DA: Neonatal detection of hypothyroidism, J PEDIATR 86:822, 1975. 3. Hobel CJ, Sack J, Cousins LM, and Fisher DA: The effect of intraamniotic thyroxine on thyroid function in the human fetus and newborn, Clin Res 25:198a, 1977. 4. Sack J, and Fisher DA: Thyroid hormone metabolism in amni0tic fluid of man and sheep, in DA Fisher, and GN Burrow, editors: Perinatal thyroid physiology and disease, New York, !975, Raven Press; pp 49-58. 5. Weichsel ME Jr: The therapeutic use of glucocorticoids in the perinatal period: Potential neurological hazards, Ann Neurol 2:364, 1977. 6. Klein A, Meltzer S, and Kenny F: Improved prognosis in congenital hypothyroidism treated before age three months, J PEDIATR81:912, 1972. 7. Raiti S, and Newns GH: Cretinism: Early diagnosis and its relation to mental prognosis, Arch Dis Child 46:692, 1971. 8. Smith DW, Blizzard RM, and Wilkins L: The mental prognosis in hypothyroidism of infancy and childhood: A review of 128 cases, Pediatrics 18:1011, 1957. 9. Nicholson JL, and Altman J: Synaptogenesis in the rat cerebellum: Effects of early hypo- and hyperthyroidism, Science 176:530, 1972. 10. Erenberg A, Omori K, Menkes JH, Oh W, and Fisher DA: Growth and development of the thyroidectomized ovine fetus, Pediatr Res 8:783, 1974. 11. Rezvani I, and DiGeorge AM: Reassessment of the daily dose of oral thyroxine for replacement therapy in hypothyroid children, J PEDIATR90:291, 1977i 12. Abbassi V, and Aldige C: Evaluation of sodium L-thyroxine (T4) requirement in replacement therapy of hypothyroidism, J PEDIATR90:298, 1977. 13. Riggs W Jr, Wilroy SR, and Etteldorf JN: Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis, and brachydactyly, Radiology 105:621, 1972. 14. Penfold JL, and Simpson DA: Premature craniosynostosis-a complication of thyroid replacement therapy, J PEDIATR 86:360, 1975.
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Editor's column
15. Dobbing J, and Sands J: Quantitative growth and development of human brain, Arch Dis Child 48:757, 1973. 16. RaafJ, and Kernohan JW: A study of the external granular layer in the cerebellum. The disappearance of the external granular layer and the growth of the molecular and internal granular layers in the cerebellum, Am J Anat 75:151, 1944. 17. Angevine JB Jr: Time of neuron origin in the hippocampal region, Exp Neurol, Suppl 2:1, 1965. 18. Altman J: Autoradiographic and histological studies of postnatal neurogenesis. II. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in infant rats, with special reference to postnatal neurogenesis in some brain regions, J Comp Neurol 128:431, 1968. 19. Bayer SA, and Altman J: Hippocampal development in the rat: Cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation, J Comp Neurol 158:55, 1974. 20. Schlessinger AR, Cowan WM, and Gottlieb DI: An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat, J Comp Neurol 159:149, 1975. 21. Altman J, and Das GD: Postnatal neurogenesis in the guinea-pig, Nature 214:1098, 1967. 22. Balfizs R, Kovacs S, Cocks WA, Johnson AL, and Eayrs JT: Effect of thyroid hormone on the biochemical maturation of rat brain: Postnatal cell formation, Brain Res 25:555, 1971. 23. Gourdon J, Clos J, Coste C, Dainat J, and Legrand J: Comparative effects of hypothyroidism, hyperthyroidism and undernutrition on the protein and nucleic acid contents of the cerebellum in the young rat, J Neurochem 21:861, 1973. 24. Nicholson JL, and Altman J: The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. 1. Cel ! proliferation and differentiation, Brain Res 44:13, 1972. 25. Weichs~l ME Jr: Effect of thyroxine on DNA synthesis and thymidine kinase activity during cerebellar development, Brain Res 78:455, 1974. 26. Clark BR, and Weichsel ME Jr: Correlation of DNA accumulation rate with thymidylate synthetase and thymidine kinase activities in developing rat cerebellum: Effect of thyroxine, J Neurochem 29:91, 1977. 27. Weichsel ME Jr: Thyroxine effect upon activity of uridine kinase in developing rat cerebellum, Biol Neonate 31:199, 1977. 28. Weichsel ME Jr: Effect of thyroxine on de novo pyrimidine biosynthesis in developing rat cerebellum, Brain Res 117:346, 1976. 29. Weichsel ME Jr, and Dawson L: Effects of hypothyroidism and undernutrition upon DNA biosynthesis and thymidine kinase activity during cerebellar development in the rat, J Neurochem 26:675, 1976. 30. Weichsel ME Jr, Clark BR, and Poland RE: Experimental hypothyroidism: relationship between cerebellar cell division and enzymes involving nucleic acid metabolism during development, Pediatr Res 11:250a, 1977.
The Journal of Pediatrics June 1978
31. Weichsel ME Jr, Clark BR, and Poland RE: Effect of hypothyroidism on aspartate transcarbamylase, uridine kinase, and DNA biosynthesis during cerebellar development in the rat, Biol Neonate 32:5, 1977. 32. Hamburgh M, Mendoza LA, Burkart JF, and Weil F: The thyroid as a time clock in the developing nervous system, in Pease DC, editor: Cellular aspects of neural growth and differentiation, UCLA Forum Medical Science, Los Angeles, 1971, University of California Press, pp 321. 33. Pelton EW, and Bass NH: Adverse effects of excess thyroid hormone on the maturation of the rat cerebrum, Arch Neurol 29:145, 1973. 34. Bakke JL, Lawrence NL, Bennett J, and Robinson S: The late effects of neonatal hyperthyroidism upon the feedback regulation of TSH secretion in rats, Endocrinology 97:659, 1975. 35. Martin JB, Boshans R, and Reichlin S: Feedback regulation of TSH secretion in rats with hypothalamic lesions, Endocrinology 87:1032, 1970. 36. Bakke JL, Lawrence N, and Wilber JF: The late effects of neonatal hyperthyroidism upon the hypothalamic-pituitarythyroid axis in the rat, Endocrinology 96:406, 1974. 37. Meserve LA, and Leathern JH: Neonatal hyperthyroidism and maturation of the rat hypothalamo-hypophysealadrenal axis, Proc Soc Exp Biol Med 147:510, 1974. 38. Weichsel ME Jr, and Poland RE: Brain development in perinatal endocrinopathies: Effect of thyroxine on serum glucocorticoid levels, Ann Neurol 2:254a, 1977. 39. Schapiro S: Some physiological, biochemical, and behavioral consequences of neonatal hormone administration: Cortisol and thyroxine, Gen Comp Endocrinol 10:214, 1968. 40. Davenport JW, and Gonzales LM: Neonatal thyroxine stimulation in rats: Accelerated behavioral maturation and subsequent learning deficit, J Comp Physiol 85:397, 1973. 41. Stone JM, and Greenough WT: Excess neonatal thyroxine: Effects on learning in infant and adolescent rats, Dev Psychobiol 8:479, 1975. 42. Eayrs JT: Effect of neonatal hyperthyroidism on maturation and learning in the rat, Anim Behav 12:195, 1964. 43. Sato T, Suzuki Y, Taketarii T, Tshiguro K, and Nakajima H: Age-related change in pituitary threshhold for TSH release during thyroxine replacement therapy for cretinism, J Clin Endocrinol Metab 44:553, 1977. 44. Bakke JL, Lawrence NL, Bennett J, and Robinson S: Endocrine syndromes produced by neonatal hyperthyroidism, hypothyroidism or altered nutrition, and effects seen in untreated progeny, in Fisher DA, and Burrow GN, editors: Perinatal thyroid physiology and disease, Kroc Foundation Symposia Series Vol 3, 1975, p 79. 45. Fisher DA: Thyroid function in the premature infant, Am J Dis Child 131:842, 1977. 46. Cuestas RA, Lindall A, and Engel RR: Low thyroid hormones and respiratory-distress syndrome of the newborn, N E n g l J Med 295:297, 1976. 47. Cuestas RA, and Engel RR: Low thyroid activity in prematures with RDS, Pediatr Res 11:424a, 1977.