0163-769X/93/1401-0094$03.00/0 Endocrine Reviews Copyright © 1993 by The Endocrine Society

Vol. 14, No. 1 Printed in U.S.A.

The Role of Thyroid Hormones in Prenatal and Neonatal Neurological Development—Current Perspectives SUSAN P. PORTERFIELD AND CHESTER E. HENDRICH Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912-3395

I. Introduction II. The Value of the Use of Animal Models in the Comprehension of the Role of Thyroid Hormones in Neurological Development III. Neurological Development in Rats and Humans IV. Prenatal Development of Thyroid Function in Rats and Humans V. Stages of Neurological Development Relative to Thyroid Function VI. The Effects of Thyroid Hormones on the Developing Brain VII. Congenital Hypothyroidism in Humans VIII. Endemic Iodine Deficiency IX. A Role for Thyroid Hormones in Fetal Development X. Placental Transport of Thyroid Hormones XI. Maternal Thyroid Hormones and Fetal Development XII. The Role of Thyroid Hormones in Phase I XIII. Summary XIV. Implications of These Data

are properly interpreted. Furthermore, most of the information obtained from animal experiments would be unavailable from humans. III. Neurological Development in Rats and Humans The rodent model is an excellent model as long as equivalent human and rodent developmental stages are compared. The rat is born early relative to brain development when compared with the human. The rat brain at 10 days postpartum is at the developmental stage equivalent to the human brain at birth (1), and the rat brain at birth is at the same stage as the human brain at 5 to 6 months of gestation (2). Consequently, stages of brain development that occur in the last trimester of human development occur postnatally in the rat. This has allowed for easy manipulation of the nutritional and endocrine environment of the developing rat brain during this important period. For this reason, a large body of the experimental data available on thyroid hormones and brain development was obtained from neonatal rats. By birth, rat cerebral neurogenesis is essentially complete with the bulk of the neurogenesis occurring between fetal day 12 and birth (3-5). While there is some formation of interneurons in the cerebrum during the first few days after birth, most of the 50% increase in cerebral cells that occurs postnatally is from glial cell proliferation. Gliogenesis essentially begins at birth in the rat and continues into adult life (4). However, in the human, where birth is later relative to neurological development, cerebral neuronal proliferation is nearly complete by the seventh month of pregnancy (6) and gliogenesis begins in utero (7). The cerebellar cortex develops later than the cerebrum; hence, 77% of the neurogenesis in the rat cerebellar cortex occurs after birth (8). Much of the equivalent cerebellar neurogenesis occurs late in fetal development in humans. The postnatal neurogenesis of the rat cerebellar cortex makes it a logical tissue for the study of thyroid hormone regulation of neurogenesis; therefore, the neonatal rat is an excellent model to study developmental events that occur in utero in humans. The neonatal period in rats is an important period for neuronal differentiation and maturation. This is a period of rapid myelinogenesis and intense proliferation and development of neuronal processes (9). This period of rapid nerve terminal formation is complete by 30 days postpartum (3). Glial cell growth and neuronal myelination occur predominantly in the period from postnatal days 10 to 45 (4). In the

I. Introduction

F

OR YEARS thyroid hormones have been known to be important for normal neonatal brain development, and numerous reviews have covered this topic in depth. It now also appears that fetal thyroid hormones play an essential role in fetal brain development. In addition, as some placental transport of thyroid hormones has been shown to occur, it is possible that maternal thyroid hormones might influence fetal brain development. II. The Value of the Use of Animal Models in the Comprehension of the Role of Thyroid Hormones in Neurological Development Animal models have been used to study the influence of thyroid hormones on neurological development. Rats and mice have been the primary animals studied; however, a significant amount of data have come from studies on sheep and nonhuman primates. While the merit of application of animal data to human problems is frequently questioned, valuable information can be obtained when the animal data Address requests for reprints to: Susan P. Porterfield, PhD., Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912-3395.

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human, while myelination begins in utero, the bulk of it occurs postnatally, and it is essentially complete by 24 months (10). IV. Prenatal Development of Thyroid Function in Rats and Humans Fisher et al. (11), have reviewed the ontogeny of thyroid function in the rat and human. Radioiodine is concentrated in the thyroid follicle by 17 days of gestation in the rat, and by 20 days the gland is actively synthesizing thyroid hormones (11). Consequently, serum T4 levels increase appreciably between day 20 and parturition in the rat fetus (12). At birth, serum TSH levels are low, but they rise rapidly to reach a peak at about 8 days postpartum (11). Likewise, serum T4 levels are low at birth but rise to a peak at about 15 days postpartum before falling to adult levels (11). In the human, the initiation of fetal thyroid hormone synthesis is frequently given as 10-12 weeks of gestation. At this time, colloid is first seen in the fetal thyroid (11, 13) and thyroid tissue is capable, in cell culture, of accumulating iodine and synthesizing thyroid hormones (14). Costa et al. (15) have shown that fetal carcass T4 is measurable at 9 weeks and increases 40-fold from 9 to 12 weeks. While the 9 week values could represent maternal hormone in the fetus, the rise in fetal T4 most likely reflects an increase in fetal hormone synthesis. However, whether significant fetal thyroid hormone synthesis occurs before 16 weeks is questionable (11). While TSH is detectable in aborted and premature fetuses by 10 weeks, according to Fisher et al. (11), serum concentration remains low until 20 weeks and then plateaus for the remainder of gestation. The rise in fetalhypothalamic-pituitary function in midgestation (16-20 weeks) leads to a rapid increase in fetal thyroid hormone secretion (11,16). More recently, human fetal blood has been obtained by cordocentesis (ultrasound-guided sampling from the umbilical cord) for thyroid hormone measurements (17). Cordocentesis allows for the determination of serum levels in fetuses that are not under extreme stress. Using this technique, Thorpe-Beeston et al. (17), obtained slightly different hormone profiles than those reported previously. Low levels of serum total T4 were measured as early as 12 weeks of gestation, and levels increased rapidly during the remainder of gestation (Fig. 1A). Serum T3 was detectable by 15 weeks, and like T4 increased progressively during gestation (Fig. IB). Serum TSH was measurable at 12 weeks and, unlike previously reported data, increased steadily during the remainder of gestation (Fig. 1C). Likewise, a steady increase in fetal serum thyroxine-binding globulin (TBG) was seen during gestation (Fig. ID). The increase in fetal serum TSH, TBG, T4, and T3 reflects the increasing maturity of the hypothalamus, pituitary, thyroid, and liver.

V. Stages of Neurological Development Relative to Thyroid Function When the development of the nervous system is analyzed with respect to the influence of thyroid hormones, three

12 20 21 I t GESTATIONAL AQE (WKS)

GESTATIONAL AQE (WKS)

12 20 2» 3« QESTATIONAL AQE (WKS)

QESTATIONAL AQE (WKS)

FIG. 1. Human fetal total T4, total T3, TSH, and TBG from serum obtained by cordocentesis. The lower limit of sensitivity of the T3 RIA is 0.2 nM. [Graphs were redrawn with permission from J. G.ThorpeBeeston et ai: N Engl J Med 324:532-536,1991 (17).]

developmental periods can be seen. Phase I is the period of development that occurs before the synthesis of fetal thyroid hormones. If the developing brain is exposed to thyroid hormones during this period, the hormones could only be maternally synthesized. This period is approximately the first 17 days of gestation in the rat and the first 10-12 weeks of gestation in the human. It is not known what direct role, if any, thyroid hormones play in neurological development during this period. Most of brainstem and a significant portion of cerebral neurogenesis occur during phase I. Neuronal migration is occurring during phase I, but significant neuronal maturation, neurite formation, and synaptic development in the forebrain do not begin until phase II. Phase II is the period in which the fetal thyroid is actively synthesizing and releasing thyroid hormones. During this period the developing fetal brain is exposed to fetal thyroid hormones and, perhaps, maternal hormones. While the importance of thyroid hormones for normal brain development late in gestation is now generally acknowledged, it is not known how important thyroid hormones are earlier in development (18). Throughout phase II, fetal brain could theoretically be directly influenced by thyroid hormones of both fetal and maternal origin. Phase III is the period after birth. During this period the brain is dependent upon thyroid hormones secreted by the neonate's thyroid. Small amounts of thyroid hormones have been shown to be present in milk (19), but the work of Mallol et al. (20) shows that previous papers suggesting that sufficient T4 is present in milk to afford some protection to the brain of a breast-fed athyrotic baby were flawed by contaminating artifacts leading to inappropriately high RIA T4 measurements. The values they measured after partial purification of the milk ranged from 0.29-2.00 /ug/liter. These levels are not likely to afford protection to the developing brain of an athyrotic baby (20). Furthermore, there is disagreement over whether there is physiologically significant transfer of these hormones to the suckling neonate (20). Phase III in rats encompasses a large portion of the period of cerebellar

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neuronal proliferation, migration, and differentiation. While forebrain neurogenesis and migration are essentially complete by this time, this is an important period for forebrain neuronal maturation, neurite outgrowth, synapse formation, and myelination. All of these events are known to be dependent upon normal thyroid hormone levels during this period (16, 18). Because the human brain is at a later developmental stage than the rat brain at the time of birth, much of the cerebellar neuronal proliferation, migration, and differentiation in humans occurs in phase II; however, they do continue into phase III. In the human, myelination begins in phase II but most gliogenesis and myelination occur after birth and hence in phase HI. The stages of brain development relative to thyroid function in the rat and the human are illustrated in Fig. 2. VI. The Effects of Thyroid Hormones on the Developing Brain There are many excellent reviews on thyroid hormones and brain development. The reader is referred to these reviews for a more thorough coverage of the topic (16, 18, 2 1 25). Investigators frequently make reference to the "critical period" in which appropriate thyroid hormone levels are absolutely essential for normal brain development. In humans, this period is generally considered to begin late in gestation and to extend through 1-2 yr of age (9). In rats, the equivalent period was originally thought to occur in the first 10-12 days postpartum (9) although it has now been expanded to encompass the period from 18 days gestation to 21 days postpartum (16, 24). In the cerebrum, this period is associated with proliferation of axons and dendrites, synapse formation, gliogenesis, and myelination (9). In the cerebellum, it includes the period encompassing the above events as well as the period of the majority of cellular proliferation. Deficiencies of thyroid hormones during this PHASE I PHASE II Maternal Maternal TH • Fetal TH (0-17dpc)(i7dpc-birth) I 1 r17 days Birth

PHASE III Neonatal TH (Birth-20 days) 20 days

10 days

Cerebral neurogenesis and migration (predominately 10-i8dpc) (Phase I, II)

h Neuronal differentiation, axonal outgrowth, dendritic ontogeny and synaptogenesis (primarily Phase III); Cerebellar neurogenesis (primarily postnatal); Gliogenesis (predominantly 4-16dpn) I Myelinogenesis (10-45dpn) (Phase III) PHASE I (0-12wks)

PHASE II (12wksterm)

12 weeks

PHASE III (Birth-1 year) Birth

1 year

Cerebral neurogenesis and migration (5-24 weeks) (Phase I, II) Neuronal differentiation, axonal outgrowth, dendritic ontogeny and synaptogenesis (Phases II and III); Cerebellar neurogenesis (predominantly prenatal); Gliogenesis (predominantly late fetal to 6 months postnatal) | Myelinogenesis (2nd trimester-2 years) (Phase II. Ill)

FIG. 2. Brain neurological development relative to thyroid function in the rat and the human. TH, Thyroid hormones; dpc, days postconception; dpn, days postnatal.

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critical period cause such serious damage to the structural development and organization of the brain that replacement therapy begun subsequent to this time can never entirely correct the damage. Most of the data presently available on thyroid hormones and brain development were obtained in rats. As thyroid hormones were once considered not essential for normal brain development in the fetal rat (18), the "critical period" in the rat was originally proposed as beginning at birth; consequently, early studies involved only neonatal rats. As cerebral neurogenesis and migration are essentially complete at birth, thyroid hormones given to the neonatal rat do not alter cerebral neurogenesis or neuronal migration. Consequently, these events were considered to occur independently of any thyroid hormone action. In actuality, these events in the cerebrum could be thyroid hormone regulated but at an earlier developmental stage. If the animal is rendered athyroid at birth, cerebral growth is impaired significantly. While there does not appear to be an effect on cerebral neuronal number, there initially is a decrease in cell number resulting from decreased gliogenesis. However, this represents merely a delay in the normal pattern in cell acquisition. The decrease in brain size in the congenitally hypothyroid rat results from an increase in cell packing rather than a decrease in cell number (3). Exposure of the rat to excess T4 at this time increases the rate of cellular proliferation in the cerebellum, a region of the brain in which significant neurogenesis occurs postnatally; this occurs because the Gl phase of mitosis is shortened which produces a phasic increase in the total number of cells (26, 27). However, as excess T4 prematurely terminates cellular proliferation, the total number of cells seen in the mature brain is actually reduced, thereby stunting brain growth, not as a result of the increased cell packing seen in hypothyroidism, but rather as a result of the decrease in the brain cell number (26, 27). It should be remembered that neurological development follows essential sequences and, while there is eventual compensation of cell numbers in hypothyroidism, the cellular composition and architecture might remain abnormal. Thyroid hormones have been proposed to act as a time clock terminating proliferation and stimulating differentiation (18). Cerebral neuronal migration is complete by birth and hence is unaltered by neonatal thyroidectomy. However, as cerebellar neuronal migration continues after birth, neonatal thyroidectomy will result in abnormal organization of the cerebellar cortex (18). The proliferative activity of the cerebellar external granular layer, which has normally almost • completely disappeared by 20 days postpartum, is still occurring at 20 days postpartum in the hypothyroid rat (28, 29). Some of the actions of thyroid hormones on brain development could be mediated through growth factors such as nerve growth factor, epidermal growth factor, and the insulin-like growth factors (30). Thyroid hormones are thought to be capable of either directly or indirectly increasing levels of these factors (31-34). Metabolic changes are seen in the brain of the thyroidectomized neonate. There is a decrease in the rate of brain

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THYROID HORMONES AND BRAIN DEVELOPMENT

protein and RNA synthesis (21, 35). In fact, Valcana and Eberhardt (36), Eayrs and Taylor (37), Szijan et al. (38), and Nicholson and Actman (29) have proposed that the mechanism whereby thyroid hormone deficiency impairs neurological development may be through its essential role as a regulator of protein synthesis. The mechanism of action of thyroid hormones as regulators of protein synthesis has been studied extensively. Thyroid hormones have been shown to regulate transcription of specific messenger RNAs, and alteration of gene expression is proposed as the mechanism whereby thyroid hormones control brain development (39, 40). There are numerous excellent reviews on the subject of the mechanism of thyroid hormone action (41-44). Thyroid hormones also have been shown to influence protein synthesis through increasing amino acid transport into brain cells (45-47), through influencing the synthesis of ribosomes and their function in translation (21, 46, 48-51), and through altering mRNA stability (44, 52). These latter effects might be secondary, rather than primary hormonal interactions. Thyroid hormones increase liver ribosomal RNA synthesis and increase liver and brain ribosomal concentration (50, 53). Ribosomal content can regulate brain protein synthesis (54). Neonatal thyroidectomy in rats results in a decrease in amino acid incorporation into protein and a decrease in brain RNA synthesis (55). Neonatal thyroid hormone deficiency causes a marked retardation in the maturational pattern of the brain-specific proteins, Dl and D2 (56). These brainspecific proteins have been implicated as playing an important role in the early stages of synaptogenesis. Balazs et al. (21), and Cocks et al. (57), have shown that the biochemical maturation of the brain is delayed in hypothyroidism. This includes: 1) retarded development of the ability to convert glucose carbon into amino acids—an index of neuronal process development; 2) reduction in succinic dehydrogenase and glutamic dehydrogenase activity—markers for nerve terminal development (8, 21); and 3) retarded development of cerebral oxidative enzymes (49). Thyroid hormones regulate gliogenesis and myelinogenesis (1, 3, 58). Neonatal hyperthyroidism accelerates, while hypothyroidism delays, the deposition of myelin (23, 58-60). In the neonatally hypothyroid rat, biosynthesis of cerebroside, sulfatide, and sphingomyelin, components of myelin, are transiently suppressed (58) while the rapid period of myelination, which normally occurs between 14 and 24 days postpartum, is delayed 4-8 days (59). Enzymes associated with myelin synthesis, such as 2',3'-cyclic nucleotide 3'phosphoesterase, myelin basic protein (arginine) methyltransferase, and galactosylceramide sulfotransferase, are regulated by thyroid hormones in the neonate (61-63). Thyroid hormones are known to regulate neuronal outgrowth and synapse formation in vivo and in cell culture (28, 35). The inability of hypothyroid neonates to show normal neuronal outgrowth is thought to be a result of abnormalities in the development of the cellular cytoskeleton (64). The cytoskeleton of the neuron consists of microfilaments, microtubules, and neurofilaments. Hypothyroidism could alter neuronal outgrowth by altering assembly, stabilization, and composition of microtubule protein (64). Normal neuronal

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process growth depends on formation of appropriate quantities of microtubules and on the normal synthesis and axonal transport of cytoskeletal components such as tubulin, microtubule associated proteins (MAPs), and neurofilament proteins (64). This role of thyroid hormones could be mediated through its action on protein synthesis. Thyroid hormones have been shown to increase the synthesis of brain tubulin protein in the fetus (65) and neonate (66). Stein et al. (5) have shown that thyroid hormones regulate the gene expression of the brain tubulin M/35 and Mai mRNA isotypes in the perinatal mouse; this effect is localized primarily to the cerebral cortex. Microtubules contain tubulin and MAPs. MAPs promote tubulin polymerization and function as linkers between microtubules and the cytoskeleton. Thyroid hormones have been shown to play a crucial role in tubulin assembly and stability (28, 67) and to regulate the expression of two specific MAPs, tau and MAP2 (68, 69). Francon et al. (68) have shown that brain microtubule formation is retarded in perinatally hypothyroid rats as a result of decreased taufactor levels. Perinatal thyroid hormone deficiency in the mouse has been shown to decrease the delivery of cytoskeletal proteins to the developing terminal via the slow component of axonal transport (64). Such changes in formation, transport, and function of components of the cytoskeleton could cause the observed impairment of neuronal process outgrowth. Hearing loss, a common problem in human endemic cretinism, is seen in rats rendered hypothyroid at birth. Poor middle ear development, characterized by incomplete ossification, as well as inner ear anatomical and physiological abnormalities, contribute to the hearing loss (25, 70). Hebert et al. (70) suggest that the critical period for auditory development begins in utero in both rats and humans. Van Middlesworth and Norris (71) have shown that feeding rats the antithyroid drug propylthiouracil during pregnancy and lactation causes severe dysfunction and disorganization of the organ of Corti and susceptibility to audiogenic seizures in their offspring. As Hebert et al. (70) have found that neonatal thyroid hormone replacement does not prevent hearing problems in 20% of children with congenital hypothyroidism, he emphasizes the importance of beginning thyroid hormone replacement therapy in utero. Behavioral testing of neonatally hypothyroid rats shows that they have retarded development of the air-righting response and the placing reflex (37), impaired learning, diminished exploratory behavior, retarded locomotor ability, and impaired maze acquisition (72). Glorieux and LaVecchio (25) have concluded that neonatal hypothyroidism results in an asynchrony of developmental events at a critical period of maturation and differentiation of the developing nervous system. Adams et al. (73) have shown that the congenitally hypothyroid (hyt/hyt) mouse has delayed ear raising and eye opening, and these delays are reversed with epidermal growth factor administration. These pups showed delayed cliff avoidance and negative geotaxis. By 40 days of age, the hyt/hyt mice showed significant retardation in locomotor activity and impaired swimming escape behavior. Such behavioral changes could suggest problems with the function

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of the corticospinal tracts, the cerebellum, the brainstem, and the vestibular system (73).

VII. Congenital Hypothyroidism in Humans Untreated congenital hypothyroidism is known to have severe effects on neurological development. The severity of the effects are correlated with the magnitude of the deficiency, the apparent time of onset of the deficiency (prenatal vs. postnatal), and the age at which appropriate replacement therapy is begun. Many of the deficits resulting from thyroid deficiency during the "critical period" cannot be entirely corrected by subsequent thyroid hormone replacement therapy. In addition to the mental retardation that can occur (1, 74), other common neurological disorders include poor coordination and balance, abnormal fine motor movements, speech problems (74), spasticity, tremor, and hyperactive deep tendon reflexes (75, 76).

VIII. Endemic Iodine Deficiency The neurological deficiencies seen in neurological endemic cretinism appear to be more severe than those resulting from sporadic congenital hypothyroidism, and the nature of the damage suggests that it is likely to have been initiated at an earlier fetal age (77). Neurological cretinism in its fully developed form is characterized by profound mental retardation, deafmutism, spastic diplegia (probably of cerebral origin), and squint (neurological cretin) (75, 78-82). Other deficiencies commonly noted are perceptual motor problems, difficulty understanding the spoken word or expressing ideas in speech, complete or partial inability to stand upright, abnormal gait in those capable of walking, a general clumsiness of movement, and poor manual dexterity (75, 80). The mental deficit appears to involve primarily problems with high-level association functions (83). The motor difficulties indicate damage to the cerebral cortex and involve both the corticospinal and rubrospinal tracts (81). It is believed that some of the damage to these children's nervous system has occurred in the first trimester—before the onset of fetal thyroid function (16, 75, 76, 84), or in the second trimester (83) when maternal and fetal hormones are important. If fetal lambs are thyroidectomized in utero, the physical impairment they show as neonates is less severe than that seen in newborns from iodine-deficient ewes (79, 85, 86). It has been proposed that iodine deficiency has more serious sequelae than congenital hypothyroidism because of the decreased availability of maternal thyroid hormones for the developing fetal brain in early and midgestation (87). This appears to be confirmed by the observation that iodine replacement in midgestation does not prevent the neurological damage (88). Pharoah et al. (89) have shown that iodized oil must be given before conception to prevent neurological damage and, hence, they conclude that an iodine deficiency in the first few months of pregnancy is critical.

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IX. A Role for Thyroid Hormones in Fetal Development Because the symptoms of hypothyroidism become much more severe after birth than they are at the time of birth, many people once thought that thyroid hormones were not essential during fetal development and their important developmental role only occurred after birth. At one time, it was generally believed that there was little transport of thyroid hormones across the placenta both in humans and rats (90-93); hence the possibility that maternal thyroid hormones might be minimizing the symptoms of fetal hypothyroidism was not necessarily considered. Hamburgh et al. (93) suggested that thyroid hormones may not contribute to rat fetal central nervous system development. Vulsma et al. (94) have shown clinical evidence that thyroid hormones do cross the placenta in humans and that sufficient placental transport occurs to appreciably decrease the symptoms of hypothyroidism occurring in the congenitally hypothyroid fetus. Thyroid hormones have also been shown to cross the placenta in rats (95-97) and as much as 17.5% of the fetal thyroid hormones at term may be of maternal origin (97). When the neonatal thyroid screening programs were begun, it was thought that if replacement therapy of the congenitally hypothyroid infant were begun within 3 months of age, permanent neurological damage could be avoided. It has since become apparent that it is crucial that treatment be initiated as soon as possible after birth. However, even when early intervention is possible, minimal brain dysfunction sometimes still occurs. Letarte and Garagorri (98) reported that 15% of treated children still have problems. These problems include behavioral problems and difficulties in practical reasoning, perceptomotor and visuomotor discrimination, spatiomotor skills, reasoning, sensorineural hearing, language comprehension, fine motor skills, and extrinsic motor eye movement (98-101). Frost (74) attributes the persistence of motor problems to sensitivity of the cerebellum to T4 in utero. While these children characteristically have an I.Q. within the normal range, there is a relative shift in the distribution of I.Q. scores toward the low side of normal (101). Glorieux and La Vecchio (25) have shown that by 36 months of age the mean global quotient (Griffiths developmental test) of the hypothyroid children was significantly lower than that of the control children with the most discriminating variable being practical reasoning. By the third grade, these children, as a group, have more problems in arithmetic, writing, and attention than their peers (100). Rovet (102) reports that at 9 yr of age 16% of treated congenitally hypothyroid children are in full-time special education classes as compared with a 1% rate for other Ontario children. These children show deficits in perceptual, neuromotor, and memory skills (Fig. 3)(102). Those children suspected of having learning problems reach 40% of the treated congenitally hypothyroid group by age 9. Fifty-four percent of the congenitally hypothyroid children are more than one-half grade delayed in learning math concepts, and only 25% are at or above grade level (102). This is confirmed by the data of Bongers-Schokking et al. (103) which show delays in neurophysiological maturation of congenitally hypothyroid

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THYROID HORMONES AND BRAIN DEVELOPMENT

100 - i

-r 80 -

T B HYPOTHYROID

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way to determine the most effective way to detect and initiate treatment of congenital hypothyroidism in utero (109, 110).

• CONTROL

Hi

6 YR 6 YR 8 YR PERCEPTUAL NEUROMOTOR MEMORY

FlG. 3. Neurocognitive deficits at 6 or 8 yr of age in congenitally hypothyroid children treated from infancy. The hypothyroid children have lower percentile scores at 6 yr (P < 0.05 for both tests) and at 8 yr (P < 0.01). The error bars reflect SD rather than SE. [Graph redrawn with permission from J. F. Rovet: Psychoneuroendocrinology—Brain, Behavior, and Hormonal Interactions (edited by C. S. Holmes), Springer-Verlag Publishers, New York, 1990, pp 273-322 (102).]

newborns at initiation of replacement therapy. These observations suggest that fetal thyroid hormones are important in utero. Since the initiation of massive neonatal thyroid screening programs, researchers have accumulated a large body of data on congenitally hypothyroid children treated after birth with thyroid hormones. Scientists have evaluated these children to establish the correlations between the severity of the permanent effects and either the time of initiation of treatment or the magnitude of the thyroid dysfunction. They found that as long as treatment was initiated within the first month of life, there did not appear to be a clear correlation between the severity of the deficits and the time therapy was initiated. They did find that there was a strong association between neurological impairment and serum T4 and bone age at birth (25, 98, 99, 104, 105). This led to the suggestion that the consequences of in utero thyroid deficiency could not be entirely averted with neonatal thyroid hormone replacement. Obviously, thyroid hormones are biologically active in both the perinate and the rodent fetus and are indeed important for normal fetal development. Stein et al. (5) have shown that the mRNAs for M/35 and Mai tubulin isotypes are lower than normal in the congenitally hypothyroid hyt/hyt mouse at the time of birth, thereby suggesting that the mRNAs may be thyroid hormone regulated in utero. If the pregnant primate is given 131I in midgestation to destroy the fetal (and maternal) thyroid, there is a decrease in fetal brain RNA and protein synthesis, thereby suggesting a role of thyroid hormones in the regulation of fetal brain protein synthesis (106). Thyroidectomized primate fetuses also have impairment of growth and epiphyseal ossification (107). These results refute the original proposal of Hamburgh (22) that thyroid hormones do not appear to have any effect on the fetus. Many researchers now emphasize the importance of eventually beginning thyroid hormone replacement therapy in utero (70, 104, 108), and research is presently under-

X. Placental Transport of Thyroid Hormones For years, it has been debated whether placental transport of thyroid hormones occurs. Experiments in which 131I is injected into the pregnant rat have been interpreted as either proving (111) or disproving (90-92) the idea of transport. Some have claimed that significant transport occurs early in gestation but not late in gestation (91, 112); others have shown that transport occurs more rapidly late in gestation than earlier (113, 114). Rat placenta has high inner ring monodeiodinase activity and hence it was proposed that thyroid hormones could not cross the placenta because they were deiodinated in passage (115). However, improved methods of hormone assay have led to confirmation and quantification of placental thyroid hormone transport. Ekins et al. (116) showed that when [125I]T4 was given to pregnant rats, by 1 h after injection, a larger percentage of the injected dose was found in the fetus than in maternal heart or brain. Sweney and Shapiro (117) were able to find labeled T4 in 13- to 14-day-old rat fetuses after injecting the tracer into the mother. They were not able to quantitate the hormone. Obregon et al. (118) measured T4 and T3 in whole rat embryos at 13 days gestation by RIA, and Porterfield and Hendrich (119, 120) have shown T4 and T3 in fetal brain as early as 12 days gestation (using the same age dating as Obregon et al.) (Fig. 4). As this is well before the initiation of fetal thyroid function, the only possible source of these hormones is the mother. Morreale de Escobar et al. (97, 121) have shown that significant transport of thyroid hormone occurs late in gestation in the rat and, just before parturition, the maternal contribution to fetal serum T4 is 17.5% even though active fetal hormone synthesis is occurring. When an injection of 50 jug T4 was given to pregnant rats on the 20th day of gestation at both 0900 h and 1600 h and maternal and fetal blood collected the next day, maternal serum T4 levels increased 8-fold and fetal levels increased 4-fold (95); the increase in fetal T4 levels suggests that while the hormone did not equilibrate across the placenta, it did cross in significant quantities. Hahn and Hassanali (122) found that treatment of the pregnant rat with T3 on the 19th and 20th days 2.0 -,

BRAIN CONTROL HYPOTHYROID

1.5 » 1.0 0.5 0.0 T4

T3

FlG. 4. Brain T4 and T3 concentrations in 13-day-old rat fetuses (12 days old if the day of conception is considered day zero) from control and hypothyroid dams. [Data reproduced with permission from S. P. Porterfield and C. E. Hendrich: Endocrinology 131:195-200, 1992 (119).® The Endocrine Society.]

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of pregnancy elevated fetal plasma T3 values and increased fetal liver phosphoenolpyruvate carboxykinase activity. In addition, administration of T4 to the pregnant rat has been shown to suppress fetal pituitary TSH (95, 123, 124). Morreale de Escobar et al. (121) have shown that if pregnant rats are treated with methimazole (MMI), an antithyroid drug that crosses the placenta, both maternal and fetal T4 and T3 are suppressed. If physiological doses of T4 are then given to the pregnant rats, fetal tissue T4 and T3 increase. They showed that T4 and T3 are available to the rat fetus from at least 3 days after implantation (125). It does, however, appear that transport is limited in that maternal and fetal hormone levels do not equilibrate; furthermore, there is insufficient transport to prevent brain damage in the athyroid human infant. A large gradient exists between mother and fetus throughout pregnancy in an euthyroid mother. Even though transport appears limited, the importance of even small quantities of maternal thyroid hormones during critical periods of fetal brain development should not be ignored. In addition, it appears in both humans (126) and rats (12) that if the mother is hypothyroid, there is net flux of thyroid hormones from the fetus to the mother late in gestation. One of the earlier groups to show placental thyroid hormone transport in humans was Grumbach and Werner (127) who, having shown transport by giving the mothers [131I]T4 and [131I]T3, concluded that significant amounts of hormone were transported but the rate was slow such that sufficient hormone could not be transported to entirely correct fetal hypothyroidism. Subsequently, Carr et al. (108) were able to successfully treat sporadic congenital hypothyroidism by administering thyroid hormone to the mother during pregnancy. Vulsma et al. (94) studied the transport of thyroid hormones in humans by evaluating the neonatal serum T4 levels of children with a total organification defect who could produce no fetal thyroid hormone (94). They measured T4 in cord blood at birth and obtained values between 35 and 70 nmol per liter (normal values are 80-170 nmol/liter). After birth, serum T4 levels decreased with a half-life of 3.6 days to levels that by 8-19 days were below the detection limit (5 nmol/liter). Vulsma et al. estimated that the maternal/fetal ratio of T4 was roughly 3:1 (See Fig. 5). The values they measured in these neonates suggest that there is significant net transfer of T4 to the fetus when the fetal thyroid is nonfunctional. These results explain the observation that the severity of the symptoms of congenital hypothyroidism rapidly increase after birth. It now appears the explanation is not that thyroid hormones were not necessary for normal fetal development, but rather that sufficient hormone is able to reach the fetus from the mother to minimize the impact of the hormone deficiency in utero and that the most severe problems occur after the maternal hormone supply is lost at birth. Data reported by these researchers totally change the manner in which thyroid problems in pregnancy are viewed and open an entirely new area of research—the role of thyroid hormones, both fetal and maternal, in normal fetal development. Calvo et al. (128), using the MMI-treated pregnant rat,

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showed that maternal administration of T4, but not T3, could correct fetal brain T3 levels. These data emphasize the importance of maternal T4 for protecting fetal brain and suggest that the fetal brain, like the adult brain, depends on serum T4, and not T3, to provide most of the tissue T3. Figure 6 shows these results. Ekins (129), has also proposed that maternal T4, but not necessarily T3, might influence fetal neurogenesis. XI. Maternal Thyroid Hormones and Fetal Development Children of women who are hypothyroxinemic during pregnancy (130-133) have, as a group, a higher incidence of behavioral and neurological disorders. The deficiencies noted are frequently those associated with minimal brain dysfunction. Additional support for the premise that maternal thyroid hormones are important for normal fetal development is provided by well-established data showing that developmental deficiencies in children with endemic iodine deficiency, in which both the mother and the fetus have a thyroid hormone deficiency, are greater than those in children with only a fetal thyroid hormone deficiency (79, 80, 134). Furthermore, if supplemental iodine is given to iodine-deficient pregnant women after the fifth month of gestation (80), the iodine does not prevent significant neurological impairment. Such iodine should be given before conception (89). Escobar del Rey et al. (135) have shown in rats that a deficiency in maternal iodine results in a deficiency in T4 and T3 in all fetal tissues studied, including brain. These data emphasize the importance of normal maternal thyroid hormone production, particularly during the first half of gestation. Maternal hypothyroidism also impairs fetal development in rats. Hypothyroid rats have prolonged gestation, and fetal and neonatal mortality is nearly 50% (136, 137). Fetuses and pups are smaller and appear to be biochemically and developmentally immature (137,138). Biochemical indices of brain development suggest that there are lags in brain cell (139), and brain ganglioside acquisition (140). Gangliosides are sometimes used as an index of synaptic development as they are concentrated in nerve terminals (141). Fetal brain DNA and protein content per brain and protein/DNA are decreased late in gestation (139); tissue glycogen deposition is impaired in the fetal and perinatal period (142); brain and liver 5'-monodeiodinase activity is low in the fetus and perinate (143-145); and perinatal brain amino acid uptake and protein synthesis are abnormally low (146). The later effect persists into adulthood. These results are substantiated by measurements of in vitro ribosomal protein synthesis that show decreased ribosomal function at most ages from late gestation to adulthood (147). Both HPLC (124) and RIA (121, 144) measurements of fetal rat brain T4 and T3 late in gestation show that the hormones are present in brain and certain other tissues in much higher concentration than in the plasma. Furthermore, if the dam is hypothyroid, fetal tissues have lower T4 and T3 levels than normal, both before (Fig. 4) and after the initiation of endogenous fetal thyroid hormone synthesis (119, 121, 124, 145).

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THYROID HORMONES AND BRAIN DEVELOPMENT

101

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Days After Birth FIG. 5. Serum T4 concentrations plotted against time after birth in neonates with a total organification defect. The open circles denote samples obtained by heel puncture, and the closed circles samples obtained by venipuncture. [Reproduced with permission from T. Vulsma et al.\ N Engl J Med 325:238-244, 1991 (125).] Brain T3

MMI

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T4 or T3 Dose Infused Cug/100 g BW/day) FIG. 6. Fetal brain T3 concentrations (at 21 days gestation) when the methimazole (MMI) treated mothers are treated with T4 or T3 in doses between 0 and 4.5 ng hormone/100 g body weight/day between days 15 and 21 of gestation. The darker shaded area corresponds to the T3 concentration in the brain of control fetuses (± SEM). The SEM values are shown as vertical lines above and below the means, unless smaller than the circles or triangles used as data points. [Reproduced with permission from R. Calvo et al.: J Clin Invest 86:889-899, 1990 (128). °The American Society for Clinical Investigation]

Behavioral testing of these pups as adults shows that these progenies have learning and memory deficiencies and show hyperactivity (137). These deficiencies resemble some of the problems reported to occur in both children of hypothyroxinemic mothers and in congenitally hypothyroid children treated with thyroid hormones since birth. Narayanan and Narayanan (148) have shown that if propylthiouracil is given to pregnant rats from day 7 of gestation, the rate of acquisition of cells in the mesencephalic and the motor nuclei of the trigeminal nerve is slowed. The final cell divisions in the motor nucleus occur between day 9 and day 10 with 88% of the cell divisions complete by day 10. Neurons of the motor nucleus normally undergo their final

cell divisions between day 9 and day 11 with 88% of the cells present by day 11. However, in the fetuses of those mothers rendered hypothyroid with propylthiouracil, only 61% of the cells in both nuclei had been formed by day 12, and cells were still forming on day 19. These data suggest that thyroid hormones (of maternal origin only before day 17-18) are important for normal cell acquisition in the mesencephalic and motor nuclei. Unless propylthiouracil is having a direct nonthyroidal action on the fetal brain, these results indicate both that thyroid hormones are crossing the rat placenta in midgestation and that these hormones are acting, in a manner analogous to their neonatal action on cerebellum, to stimulate neuronal cell proliferation. Potter et al. (85) have shown in sheep that the lack of maternal thyroid hormones in early pregnancy causes a reduction in brain growth in the fetus which is restored to normal after the onset of fetal thyroid function. The slower brain growth in midgestation included the cerebrum as well as the cerebellum and brainstem, thereby suggesting that thyroid hormones might regulate cerebral and brainstem cellular proliferation as it is known to do later in gestation in the cerebellum. The exact cause of the fetal impairment resulting from maternal hypothyroidism is not known. Maternal hypothyroidism could alter fetal development indirectly by altering maternal metabolism such that fetal nutrient availability is compromised (142, 149, 150). Furthermore, placental function could be altered by direct action on the placenta or by indirect action on placental blood flow. Circulating levels of many hormones, including GH and some of the growth factors, are altered in hypothyroidism and such alterations could affect fetal development. In addition, recent evidence

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mentioned above indicates that maternal thyroid hormones cross the placenta in both humans and rats and therefore could play a direct role in fetal development. XII. The Role of Thyroid Hormones in Phase I The importance of neonatal thyroid hormones for normal brain development in phase III has been known for years. It is now recognized that thyroid hormones are important for normal brain development in phase II, but the source of all of the hormones is still debatable. Thyroid hormones of both maternal and fetal origin may play a role at this time. The newest avenue of study is the role, if any, of thyroid hormones in phase I. Any hormones found in the fetus at this time would, of necessity, be of maternal origin. It now appears that thyroid hormones are present and probably functional in the fetal brain before endogenous hormone synthesis. The presence of these hormones, as well as their receptors, has been shown both in rats (118, 124, 151) and in humans (152-155). Mellstrom et al. (156) have shown the presence of ai-mRNA in the 14 day fetal rat brain and that the mRNA is developmentally regulated. Obregon et al. (118) have detected T4 and T3 by RIA in 10- to 12-dayold rat embryo trophoblasts, and in 13- to 20-day-old embryos. Porterfield and Hendrich (119, 124) have been able to measure by HPLC, both T3 and T4 in the 12- to 13-dayold fetal rat brain and have shown that brain selectively accumulates thyroid hormones at this age. Even though T3 levels are thought to be low in the fetus and measurements of fetal serum T3 by RIA or HPLC show it to be very low, even just before parturition, fetal brain and liver T3 are high relative to T4 (119, 124, 144, 145). These data suggest that T3 is probably an important thyroid hormone in the fetus and that 5'-monodeiodinase plays a major role in fetal tissue thyroid hormone action as has been shown in the postnatal rat (157). Furthermore, thyroid hormone receptors have been detected in the fetal rat carcass as early as 13 days of gestation and in fetal brain as early as 14 days of gestation (151, 152). Some have questioned whether the hormones have any biological action so early in gestation (93), but the work of Narayanan and Narayanan (148) would suggest otherwise. If the pregnant ewe is maintained on an iodine-deficient diet, such that her serum T4 and T3 levels are 30-50% of normal, fetal development is severely retarded, and brain weight and DNA content are reduced both at 70 and at 80 days gestation (16). At 70 days, the reduction indicates impaired neurogenesis, while at 80 days it indicates deficient glial cell multiplication (16). If, instead, the fetus of a normal mother is thyroidectomized between days 50 and 60 of gestation (the time of onset of thyroid function in the lamb), the cerebral changes are not as severe. Thyroidectomy of the ewe before pregnancy results in retarded fetal brain growth until about 125 days of gestation followed by "catch-up" growth late in gestation (16, 85). This period of brain growth retardation would correspond to phase I and would suggest that maternal thyroid hormones are important during this period in sheep for normal neuroblast multiplication. This "catch-up" growth obviously occurred after fetal thyroid hormones were available. In the iodine-deficient fetal lamb,

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fetal thyroid hormones were not available to allow for this "catch-up" growth and hence the neurological impairment was greater because it involved both phase I and phase II. Thyroid hormones have also been measured in the human fetus by 10 weeks of gestation (153-155). This early in gestation, these hormones are not likely of fetal origin. Furthermore, thyroid hormone receptors have been shown by this age (152-154). While these data do not prove a biological action for thyroid hormones early in development, there is no reason to doubt an action. The observation that iodine replacement in iodine-deficient women in midgestation is too late to prevent fetal brain damage suggests that thyroid hormones could indeed be as important for the human fetus as they are for the rat (88). XIII. Summary For years scientists have known that thyroid hormones are essential for normal neonatal brain development in both humans and rodents. Furthermore, data obtained in followup studies of neonatal thyroid screening programs support the idea that fetal thyroid hormones are important for normal fetal brain development late in gestation. It now appears that there is at least minimal thyroid hormone transport from the mother to the fetus and that the fetal brain is, indeed, exposed to thyroid hormones before the initiation of fetal thyroid hormone synthesis. In addition, thyroid hormone receptors have been demonstrated to be present during this period. Whether the receptors are functional and whether the developing brain actually requires thyroid hormones for normal development during this period remains to be proven. However, clinical evidence obtained from studying children in iodine-deficient regions would suggest that thyroid hormones are indeed important for normal brain development during the first half of gestation. Experimental results obtained in rodents and sheep would also support this proposal. XIV. Implications of These Data If it is proven that thyroid hormones of maternal origin are directly essential for normal brain development early in gestation, what are the implications? Because much of brain stem and cerebral neurogenesis occurs in the first and second trimester, periods when thyroid hormones were once thought to be unavailable to the fetal brain, these events have not been considered to be thyroid hormone dependent. Is it logical to expect thyroid hormones to have such profound effects later in development on these events in the cerebellum and assume they truly do nothing in the brainstem and cerebrum? While, admittedly, the brain levels of T4 and T3 are extremely low early in gestation, even low levels of the hormones could have important developmental roles. Until recently, it was not possible to measure the low levels of hormone present at this time and hence it was erroneously assumed they were not present. We know that protein synthesis is a crucial process for normal tissue growth and development as well as maintenance. Furthermore, thyroid hormones are known to have

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February, 1993

THYROID HORMONES AND BRAIN DEVELOPMENT

important actions as regulators of both transcription and translation. It has frequently been proposed that the actions of thyroid hormones on both brain development and neurological function might result from thyroid hormones' actions on protein synthesis. Is there any reason to think that protein synthesis, a crucial function in developing tissues, is not regulated by thyroid hormones in the first trimester as it is later in development? Growth factors such as epidermal growth factor, nerve growth factor, and insulin-like growth factors have been proposed to play important roles in neurological development. Likewise, thyroid hormones have been proposed as regulators of these essential compounds. Could thyroid hormones alter brain development through changes in synthesis or action of one or more of these growth factors? Levels of some nonthyroidal hormones such as insulin are reduced in the fetuses of hypothyroid mothers. Could neurological damage resulting from an in utero thyroid hormone deficiency be exacerbated by altered levels of critical nonthyroidal hormones? If, indeed, maternal thyroid hormones have any direct action on the development of fetal brain, the implications for maternal management could be significant. Such a development would require very precise maintenance of appropriate maternal thyroid hormone levels in all pregnant women with thyroid disorders (125).

13. 14. 15.

16.

17.

18.

19. 20. 21.

22. References 1. Bass NH, Pelton EW, Young E 1977 Defective maturation of cerebral cortex: an inevitable consequence of dysthyroid states during early postnatal life. In: Grave GD (ed) Thyroid Hormones and Brain Development. Raven Press, New York, pp 199-214 2. Eayrs JT 1968 Developmental relationship between brain and 1 thyroid. In: Michael RP (ed) Endocrinology and Human Behavior. Oxford University Press, London, pp 239-255 3. Balazs R 1973 Hormonal influences on brain development. In: Himivich W (ed) Biochemistry of the Developing Brain. Marcel Dekker, Inc, New York, vol 1:39-63 4. Berry M 1974 Development of the cerebral neocortex of the rat. In: Gottlieb G (ed) Studies on the Development of Behavior and the Nervous System: Aspects of Neurogenesis. Academic Press, New York, vol 2:7-67 5. Stein SA, Shanklin DR, Adams PM, Mihailoff GM, Palnitkar MB, Anderson B 1989 Thyroid hormone regulation of specific mRNAs in the developing brain. In: Delong GR, Robbins J, Condliffe PG (eds) Iodine. Plenum, New York, pp 59-78 6. Zamenhof S, Van Marthens E 1971 Hormonal and nutritional aspects of prenatal brain development. In: Pease DC (ed) Cellular Aspects of Neuronal Growth and Differentiation. University of California Press, Berkeley, pp 329-355 7. Dobbing J, Sands J 1973 Quantitative growth and development of human brain. Arch Dis Child 48:757-767 8. Balazs R, Richter D 1973 Effects of hormones on the biochemical maturation of the brain. In: Himivich W (ed) Biochemistry of the Developing Brain. Marcel Dekker, Inc, New York, vol 1:253-299 9. Oklund S, Timiras PS 1977 Influences of thyroid levels in brain ontogenesis in vivo and in vitro. In: Grave GD (ed) Thyroid Hormones and Brain Development. Raven Press, New York, pp 33-47 10. Jacobson MD 1985 Developmental Neurobiology, ed 2. Plenum, New York 11. Fisher DA, Dussault JH, Sack J, Chopra IJ 1977 Ontogenesis of hypothalamic-pituitary-thyroid function and metabolism in man, sheep and rat. Rec Prog Horm Res 33:59-116 12. Porterfield SP, Hendrich CE 1981 Alterations of serum thyroxine,

23. 24. 25.

26. 27. 28. 29. 30. 31. 32.

33.

34. 35.

103

triiodothyronine and thyrotropin in the progeny of hypothroid rats. Endocrinology 108:1060-1063 DeGroot LJ, Larsen PR, Refetoff S, Stanbury JB 1984 The Thyroid and Its Diseases, ed 5. Wiley Medical Publishers, New York, p 7 Shepard TH 1967 Onset of function in the human fetal thyroid: biochemical and radiographic studies from organ culture. J Clin Endocrinol Metab 27:945-958 Costa A, Arisio R, Benedetto C, Bertino E, Fabris C, Giraudi G, Marozio L, Maula V, Pagliano M, Testori O, Zoppetti G 1991 Thyroid hormones in tissues from human embryos and fetuses. J Endocrinol Invest 14:559-568 Morreale de Escobar G, Escobar del Rey F, Ruiz-Marcos A 1983 Thyroid hormone and the developing brian. In: Dussault JH, Walker P (eds) Congenital Hypothyroidism. Marcel Dekker, Inc, New York, pp 85-127 Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM 1991 Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 324:532-536 Hamburgh M, Mendoza LA, Burkart JF, Weil F 1971 The thyroid as a time clock in the developing nervous system. In: Pease DC (ed) Cellular Aspects of Neural Growth and Differentiation. University of California Press, Berkeley, pp 321-328 Nizankowska-Blaz T, Abramowicz T, Korczowski R, Rusin J 1988 Triiodothyronine and thyroxine in human, cow's and formula milk. Exp Clin Endocrinol 91:116-118 Mallol J, Obregon MJ, Morreale de Escobar G 1982 Analytical artifacts in radioimmunoassay of L-thyroxin in human milk. Clin Chem 28:1277-1282 Balazs R, Cocks WA, Eayrs JT, Kovacs S 1971 Biochemical effects of thyroid hormones on the developing brain. In: Hamburch M, Barrington EJW (eds) Hormones in Development. Appleton-Century-Crofts, New York, pp 357-379 Hamburgh M 1969 The role of thyroid and growth hormones in neurogenesis. In: Moscona A, Monroy A (eds) Current Topics in Developmental Biology. Academic Press, New York, vol 4:109148 Legrand J 1982 Hormones thyroidiennes et maturation du systeme nerveu. J Physiol Paris 78:603-652 Dussault JH, Ruel J 1987 Thyroid hormones and brain development. Annu Rev Physiol 49:321-334 Glorieux J, LaVecchio FA 1983 Psychological development in congenital hypothyroidism. In: Dussault JH, Walker P (eds) Congenital Hypothyroidism. Marcel Dekker, Inc, New York, pp 411— 430 Lauder JM 1977 Effects of thyroid state on development of rat cerebellar cortex. In: Grave GD (ed) Thyroid Hormone and Brain Development. Raven Press, New York, pp 235-254 Lauder JM 1977 The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex III. Kinetics of cell proliferation in the external granular layer. Brain Res 126:31-51 Nunez J 1984 Effects of thyroid hormones during brain differentiation. Mol Cell Endocrinol 37:125-132 Nicholson JL, Actman J 1972 The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation. Brain Res 44:13-23 Timiras PS, Nzekwe EU 1989 Thyroid hormones and nervous system development. Biol Neonate 55:376-385 Marek J, Schullerova M, Schreiberova O, Limanova Z 1981 Effect of thyroid function on serum somatomedin activity. Acta Endocrinol (Copenh) 96:491-497 Binoux M, Faivre-Bauman A, Lassarre C, Barret A, Tixier Vidal A 1985 Triiodothyronine stimulates the production of insulin-like growth factors (IGF) by fetal hypothalamus cells cultured in serumfree medium. Brain Res 353:319-321 Miller MJ, Fels EC, Shapiro LE, Surks MI 1987 L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone producing cell line. J Clin Invest 79:1773-1781 Walker P, Weichsel ME, Fisher DA, Guo SM 1979 Thyroxine increases nerve growth factor concentration in adult mouse brain. Science 204:427-429 Legrand C, Clos J, Legrand J 1982 Influence of altered thyroid

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 January 2017. at 10:29 For personal use only. No other uses without permission. . All rights reserved.

104

36.

37. 38.

39. 40.

41. 42. 43. 44.

45. 46.

47.

48. 49.

50.

51. 52.

53. 54. 55.

PORTERFIELD AND HENDRICH and nutritional states on early histogenesis of the rat cerebellar cortex with special reference to synaptogenesis. Reprod Nutr Dev 22[SuppllB]:201-208 Valcana T, Eberhardt NL 1977 Effects of neonatal hypothyroidism on protein synthesis in the developing rat brain: an open question. In: Grave GD (ed) Thyroid Hormones and Brain Development. Raven Press, New York, pp 271-286 Eayrs JT, Taylor SH 1951 The effect of thyroid deficiency induced by methyl thiouracil on the maturation of the central nervous system. J Anat 85:350-358 Szijan I, Kalbermann IE, Gomez CJ 1971 Hormonal regulation of brain development. IV. Effect of neonatal thyroidectomy upon incorporation in vivo of L-(3H) phenylalanine into proteins of developing rat cerebral tissues and pituitary gland. Brain Res 27:309-318 Munoz A, Rodriguez-Pena A, Perez-Castillo A, Ferreiro B, Sutcliffe JG, Bernal J 1991 Effects of neonatal hypothyroidism on rat brain gene expression. Mol Endocrinol 5:273-280 Stein SA, Adams PM, Shanklin DR, Mihailoff GA, Palnitkar MB 1991 Thyroid hormone control of brain and motor development: molecular, neuroanatomical, and behavioral studies. In: Bercu BB, Shulman DI (eds) Advances in Perinatal Thyroidology. Plenum Press, New York, pp 47-105 DeGroot LJ 1991 Mechanism of thyroid hormone action. In: Bercu BB, Shulman DI (eds) Advances in Perinatal Thyroidology. Plenum Press, New York, pp 1-10 Samuels HH, Forman BM, Horowitz ZD, Ye ZS 1989 Regulation of gene expression by thyroid hormone. Annu Rev Physiol 51:623:639 Oppenheimer JH, Schwartz HL, Mariash CN, Kinlaw WB, Freake HC 1987 Advances in our understanding of thyroid hormone action at the cellular level. Endocr Rev 8:288-308 Nunez J 1988 Mechanism of action of thyroid hormone. In: Cooke BA, King RJB, van der Molen HJ, (eds) Hormones and Their Actions, Part I. Elsevier Science Publishers, Amsterdam, Biomedical Division, pp 61-80 Daniel PM, Love ER, Pratt OE 1975 Hypothyroidism and amino acid entry into brain and muscle. Lancet 2:872 Pickard MR, Sinha AK, Gullo D, Patel N, Hubank M, Ekins RP 1987 The effect of 3,5,3'-triiodothyronine on leucine uptake and incorporation into protein in cultured neurons and subcellular fractions of rat central nervous system. Endocrinology 121:20182026 Geel SE, Valcana T, Timiras P 1967 Effect of neonatal hypothyroidism and of thyroxine on L-[14C] leucine incorporation in protein in vivo and the relationship to ionic levels in the developing brain of the rat. Brain Res 4:143-150 Sokoloff L, Kaufman S, Campbell PL, Francis CM, Gelboin H 1963 Thyroxine stimulation of amino acid incorporation into protein. Localization of stimulated step. J Biol Chem 238:1432-1437 Sokoloff L, 1977 Biochemical mechanisms of the action of thyroid hormones: relationship to their role in brain. In: Grave GD (ed) Thyroid Hormones and Brain Development. Raven Press, New York, pp 73-91 Hendrich CE, Porterfield SP, Evidence that brain rRNA levels and brain ribosomal incorporation of amino acids into protein are dependent upon both maternal and fetal thyroid hormone. Program of the 66th Annual Meeting of the American Thyroid Association, Boston, MA, 1991 (Abstract 577) Tata JR 1980 The action of growth and developmental hormones. Biol Rev 55:285-319 Diamond DJ, Goodman HM 1985 Regulation of growth hormone messenger RNA synthesis by dexamethasone and triiodothyronine—transcriptional rate and mRNA stability changes in pituitary tumor cells. J Mol Biol 181:41-62 Smith-Gill SJ, Carver V 1981 Biochemical characterization of organ differentiation and maturation. In: Gilbert LI, Frieden E (eds) Metamorphosis. Plenum Press, New York, pp 491-544 Dunlop DS, Kaufman DS, Lajtha A 1991 The relation of protein synthesis to the concentrations of free and membrane-bound ribosomes in brain at different ages. Neurochem Int 19:601-603 Kohl HH 1972 Depressed RNA synthesis in the brains and livers

56. 57. 58.

59.

60.

61. 62.

63.

64.

65. 66. 67. 68. 69.

70. 71. 72. 73.

74. 75.

76.

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of thyroidectomized, normal and hormone injected rats. Brain Res 40:445-458 Patel AJ, Hunt A, Meier E 1985 Effects of undernutrition and thyroid state on the ontogenetic changes of DI, D2 and D3 brainspecific proteins in rat cerebellum. J Neurochem 44:1581-1587 Cocks JA, Balazs R, Johnson AL, Eayrs JT 1970 Effect of thyroid hormone on the biochemical maturation of rat brain: conversion of glucose-carbon into amino acids. J Neurochem 17:1275-1285 Tsujimura R, Kariyama N, Hatotani N 1971 Disturbances of myelination in neonatally thyroidectomized rat brains. In: Lissak K (ed) Hormones and Brain Function. Plenum Press, New York, pp 69-78 Rosman NP, Malone MJ 1977 Brain myelination in experimental hypothyroidism: Morphological and biochemical observations. In: Grave GD (ed) Thyroid Hormones and Brain Development. Raven Press, New York, pp 169-198 Koper JW, Hoeben RC, Hochstenbach FMH, van Golde LMG, Lopes-Cardozo M 1986 Effects of triiodothyronine on the synthesis of sulfolipids by oligodendrocyte-enriched glial cultures. Biochim Biophys Acta 887:327-334 Almazan G, Honegger P, Matthieu J 1985 Triiodothyronine stimulation of oligodendroglial differentiation and myelination. Dev Neurosci 7:45-54 Amur SG, Shanker G, Pieringer RA 1984 Regulation of myelin basic protein (arginine) methyltransferase by thyroid hormone in myelinogenic cultures of cells dissociated from embryonic mouse brain. J Neurochem 43:494-498 Ferret-Sena V, Sena A, Besnard F,, Fressinaud C, Rebel G, Sarlieve LL 1990 Comparison of the mechanisms of action of insulin and triiodothyronine on the synthesis of cerebroside sulfotransferase in cultures of cells dissociated from brains of embryonic mice. Dev Neurosci 12:89-105 Stein SA, Kirkpatrick LL, Shanklin DR, Adams PM, Brady ST 1991 Hypothyroidism reduces the rate of slow component A (SCa) axonal transport and the amount of transported tubulin in the hyt/ hyt mouse optic nerve. J Neurosci Res 28:121-133 Takahashi T 1983 Transplacental effects of 3,5-dimethyl-3'-isopropyl-L-thyronine on tubulin content in fetal brains in rats. Jpn J Physiol 34:365-368 Chaudhury S, Chatterjee D, Sarkar PK 1985 Induction of brain tubulin by triiodothyronine: dual effect of the hormone on the synthesis and turnover of the protein. Brain Res 339:191-194 Seiger A, Granholm A 1981 Thyroxin dependency of the developing locus coeruleus. Cell Tissue Res 220:1-15 Francon J, Fellous A, Lennon AM, Nunez J 1977 Is thyroxine a regulatory signal for neurotubule assembly during brain development? Nature 266:188-190 Benjamin S, Cambray-Deakin MA, Burgoyne RD 1988 Effect of hypothyroidism on the expression of three microtubule-associated proteins (1A, IB and 2) in developing rat cerebellum. Neuroscience 27:931-939 Hebert R, Langlois JM, Dussault JH 1985 Permanent defects in rat peripheral auditory function following perinatal hypothyroidism: determination of a critical period. Dev Brain Res 23:161-170 Van Middlesworth L, Norris CH 1980 Audiogenic seizures and cochlear damage in rats after perinatal antithyroid treatment. Endocrinology 106:1686-1690 Essman WB, Mendoza LA, Hamburgh M 1968 Critical periods of maze acquisition development in euthyroid and hypothyroid rodents. Psychol Rep 23:795-800 Adams PM, Stein SA, Palnitkar M, Anthony A, Gerrity L, Shanklin DR 1989 Evaluation and characterization of the hypothyroid hyt/hyt mouse I: somatic and behavioral studies. Neuroendocrinology 49:138-143 Frost GJ 1986 Aspects of congenital hypothyroidism. Child Care Health Dev 12:369-375 Querido A, Bleichrodt N, Djokomoeljanto R 1978 Thyroid hormones and human mental development. In: Corner MA, Baker RE, Van de Pol NE, Swaab DF, Uylings HBM (eds) Progress in Brain Research. Elsevier, Amsterdam, vol 48:337-346 Smith DW, Blizzard RM, Wilkins L 1957 The mental prognosis in hypothyroidism of infancy and childhood. Pediatrics 19:10111022

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February, 1993

THYROID HORMONES AND BRAIN DEVELOPMENT

77. Escobar del Rey F, Mallot J, Pastor R, Morreale de Escobar G 1987 Effects of maternal iodine deficiency on thyroid hormone economy of lactating dams and pups: maintenance of normal cerebral 3,5,3'-triiodo-l-thyronine concentrations in pups during major phases of brain development. Endocrinology 121:803-811 78. Hetzel BS 1983 Iodine deficiency disorders and their eradication. Lancet 2:1126-1129 79. Hetzel BS, Potter BJ 1985 A review of animal models for the study of the effects of iodine deficiency on brain development. In: Kochupillai N, Karmarkar MG, Ramaligaswami V (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, pp 256-323 80. Fierro-Benitez R, Rameriz I, Garces J, Jaramillo C, Moncayo F, Stanbury JB 1974 The clinical pattern of cretinism as seen in highland Ecuador. Am J Clin Nutr 27:531-543 81. Stanbury JP, 1984 The pathogenesis of endemic cretinism. J Endocrinol Invest 7:409-419 82. MacFaul R, Dorner S, Brett EM, Grant DB 1978 Neurological abnormalities in patients treated for hypothyroidism from early life. Arch Dis Child 53:611-619 83. Delong GR 1985 Neurological assessment of endemic cretinism in Ecuador and Zaire. In: Kochupillai N, Karmarkar MG, Ramaligaswami (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, pp 34-40 84. Gonnolly KJ 1985 Psychological evaluation of developmental disorders associated with iodine deficiency. In: Kochupillai N, Karmarkar MG, Ramaligaswami V (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, pp 317-323 85. Potter BJ, Mclntosh GH, Mano MT, Baghurst PA, Chavadej J, Hua CH, Cragg BG, Hetzel BS 1986 The effect of maternal thyroidectomy prior to conception on foetal brain development in sheep. Acta Endocrinol (Copenh) 112:93-99 86. Potter BJ, Mclntosh GH, Hetzel BS 1981 The effect of iodine deficiency on fetal brain development in the sheep. In: Hetzel BS, Smith RM (eds) Fetal Brain Disorders. Recent Approaches to the Problem of Mental Deficiency. Elsevier/Horth Holland Biomedical Press, Amsterdam, pp 119-148 87. Ferreiro B, Bernal J, Potter BJ 1987 Ontogenesis of thyroid hormone receptor in foetal lambs. Acta Endocrinol (Copenh) 116:205-210 88. Fierro-Benitez R, Ramirez I, Suarez J 1972 Effect of iodine correction early in fetal life on intelligence quotient. A preliminary report. In: Stanbury JB, Kroc RL (eds) Human Development and the Thyroid Gland. Plenum Press, New York, pp 239-247 89. Pharoah POD, Buttfield IH, Hetzel BS 1971 Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1:308-310 90. Dussault JH, Coulombe P 1980 Minimal placental transfer of Lthyroxine (T4) in the rat. Pediatr Res 14:228-231 91. Fisher DA, Lehman H, Lackey C 1964 Placental transport of thyroxine. J Clin Endocrinol 24:393-400 92. Dubois JD, Cloutier A, Walker P, Dussault JH 1977 Absence of placental transfer of L-triiodothyronine (T3) in the rat. Pediatr Res 11:116-119 93. Hamburgh M, Lynn E, Weiss EP 1964 Analysis of the influence of thyroid hormone on prenatal and postnatal maturation of the rat. Anat Rec 150:147-162 94. Vulsma T, Gons MH, de Vijlder J 1989 Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect of thyroid agenesis. N Engl J Med 321:13-16 95. Porterfield SP 1985 Prenatal exposure of the fetal rat to excessive L-thyroxine or 3,5-dimethyl-3'-isopropyl-L-thyronine produces persistent changes in the thyroidal control system. Horm Metab Res 17:655-659 96. Morreale de Escobar G, Obregon MJ, Escobar del Rey F 1988 Transfer of thyroid hormones from the mother to the fetus. In: Delang F, Fisher DA, Glinoer D (eds) Research in Congenital Hypothyroidism, Plenum Press, New York, pp 15-28 97. Morreale de Escobar G, Calvo R, Obregon MJ, Escobar del Rey F 1990 Contribution of maternal thyroxine to fetal thyroxine pools in normal rats near term. Endocrinology 126:2765-2767 98. Letarte J, Garagorri JM 1989 Congenital hypothyroidism: labo-

99. 100.

101. 102.

103.

104. 105.

106. 107. 108.

109. 110. 111. 112. 113. 114. 115.

116.

117. 118.

119.

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ratory and clinical investigation of early detected infants. In: Collu R, Ducharme JR, Guyda HJ (eds) Pediatric Endocrinology. Raven Press Ltd, New York, pp 449-471 Glorieux J, Desjardens M, Letarte J, Morissette J, Dussault J 1988 Useful parameters to predict the eventual mental outcome of hypothyroid children. Pediatr Res 24:6-8 Rovet J, Ehrlich R, Sorbara D, Czuchta D, Neurodevelopmental profiles of children with congenital hypothyroidism (CH) diagnosed by newborn screening. Presented at International Symposium on Advances in Perinatal Thyroidology, Longboat Key, FL, 1990 (Abstract 10) Rovet JF 1986 A prospective investigation of children with congenital hypothyroidism identified by neonatal thyroid screening in Ontario. Can J Public Health 77:164-173 Rovet JF 1990 Congenital hypothyroidism: Intellectual and neuropsychological functioning. In: Holmes CS, (ed) Psychoneuroendocrinology—Brain, Behavior, and Hormonal Interactions. Springer-Verlag, New York, pp 273-322 Bongers-Schokking CJ, Colon EJ, Hoogland RA, de Groot CJ, Van den Brande JL 1991 Somatosensory evoked potentials in neonates with primary congenital hypothyroidism during the first week of therapy. Pediatr Res 30:34-39 Virtanen M, Maenpaa J, Santavouri P, Hirvonen E, Peheentupa J 1983 Congenital hypothyroidism: age at start of treatment versus outcome. Acta Pediatr Scand 72:197-201 Glorieux J, Dussault JH, Letarte J, Guyda H, Morissette J 1983 Preliminary results on the mental development of hypothyroid infants detected by the Quebec Screening Program. J Pediatr 102:19-22 Holt AB, Cheek DB, Kerr GR 1973 Prenatal hypothyroidism and brain composition in primates. Nature 243:413-414 Kerr GR, Tyson IB, Allen JR, Wallace JH, Scheffler G 1972 Deficiency of thyroid hormone and development of the fetal rhesus monkey. Biol Neonate 21:282-295 Carr EA, Beierwaltes WH, Raman G, Dodson VN, Tanton J, Betts JS, Stambaugh RA 1959 The effect of maternal thyroid function on fetal thyroid function and development. J Clin Endocrinol Metab 19:1-18 Lightner ES, Fisher DA, Giles H, Woolfenden J 1977 Intraamniotic injection of thyroxine (T4) to a human fetus. Evidence for conversion of T4 to reverse T3. Am J Obstet Gynecol 127:487-490 Perelman AH, Johnson RL, demons RD, Finberg HJ, Clewell WH, Trujillo L 1990 Intrauterine diagnosis and treatment of fetal goiterous hypothyroidism. J Clin Endocrinol Metab 71:618-621 Gray B, Galton VA 1982 The transplacental passage of thyroxine and foetal thyroid function in the rat. Acta Endocrinol (Copenh) 75:725-733 Woods RJ, Sinha AK, Ekins RP 1984 Uptake and metabolism of thyroid hormones by the rat foetus in early pregnancy. Clin Sci 67:359-363 Natif B, Sfez M, Michel R, Roche J 1956 Sur la permeabilite du placenta a la L-3:5:3'-triiodothyronine. C R Soc Biol (Paris) 150:1088-1090 Hamburgh M, Sobel EH, Koblin R, Rinestone A 1962 Passage of thyroid hormone across the placenta in intact and hypophysectomized rats. Anat Rec 144:219-227 Roti E, Braverman LE, Fang S, Alex S, Emerson CH 1982 Ontogenesis of placental inner ring thyroxine deiodinase and amniotic fluid 3,3',5'-triiodothyronine concentration in the rat. Endocrinology 111:959-963 Ekins RP, Sinha AK, Woods RJ 1985 Maternal thyroid hormones and development of the foetal brain. In: Kochupillai N, Karmarkar MG, Ramaligaswami V (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, India, pp 222-245 Sweney LR, Shapiro BL 1975 Thyroxine and palatal development in the rat. Dev Biol 42:19-27 Obregon MJ, Mallol J, Pastor R, Morreale de Escobar G, Escobar del Rey F 1984 L-Thyroxine and 3,5,3'-triiodo-L-thyronine in rat embryos before onset of fetal thyroid function. Endocrinology 114:305-307 Porterfield SP, Hendrich CE 1992 Tissue iodothyronine levels in

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120.

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126. 127. 128. 129. 130.

131.

132.

133. 134. 135.

136. 137.

138.

PORTERFIELD AND HENDRICH fetuses of control and hypothyroid rats at 13 and 16 days gestation. Endocrinology 131:195-200 Porterfield SP, Hendrich CE, Mid-gestational iodothyronines in brain, liver and carcass of fetuses of control and hypothyroid (Tx) rats. Program of the 72th Annual Meeting of The Endocrine Society, Atlanta, GA, 1990, p 386 (Abstract 1452) Morreale de Escobar G, Obregon MJ, Ruiz de Ona C, Escobar del Rey 1988 Transfer of thyroxine from the mother to the rat fetus near term: effects on brain 3,5,3'-triiodothyronine deficiency. Endocrinology 122:1521-1531 Hahn P, Hassanali S 1982 The effect of 3,5,3'-triiodo-thyronine on phosphoenolpyruvate carboxykinase fatty acid synthetase and malic enzyme activity of liver brown fat of fetal and neonatal rats. Biol Neonate 41:1-7 Bockers TM, Sourgens H, Wittkowski W, Jekat A, Pera F 1990 Changes in TSH-immunoreactivity in the pars tuberals and pars distalis of the fetal rat hypophysis following maternal administration of propylthiouracil and thyroxine. Cell Tissue Res 260:403408 Porterfield SP, Hendrich CE 1991 The thyroidectomized pregnant rat—an animal model to study fetal effects of maternal hypothyroidism. In: Bercu B, Shulman D (eds) Advances in Perinatal Thyroidology. Plenum, New York, pp 107-132 Morreale de Escobar G, Pastor R, Obregon MJ, Escobar del Rey F 1985 Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. Endocrinology 117:1890-1900 Kennedy AL, Montgomery DAD 1978 Hypothyroidism in pregnancy. Br J Obstet Gynaecol 85:225-230 Grumbach MM, Werner SH 1956 Transfer of thyroid hormone across the human placenta at term. J Clin Endocrinol 16:13921395 Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F, Morreale de Escobar G 1990 Congenital hypothyroidism as studied in rats. J Clin Invest 86:889-899 Ekins R 1985 Roles of serum thyroxine-binding proteins and maternal thyroid hormones in fetal development. Lancet 1:1129— 1132 Man EB, Holden RH, Jones WS 1971 Thyroid function in human pregnancy. VII. Development and retardation of 4-year-old progeny of euthyroid and of hypothyroxinemic women. Am J Obstet Gynecol 109:12-18 Man EB, Jones WS 1969 Thyroid function in human pregnancy. V. Incidence of maternal serum low butanol-extractable iodines and of normal gestational TBG and TBPA capacities; retardation of 8-month-old infants. Am J Obstet Gynecol 104:898-908 Jones WS, Man EB 1969 Thyroid function in human pregnancy. IV. Premature deliveries and reproductive failures of pregnant women with low serum butanol-extractable iodines. Maternal serum TBG and TBPA capacities. Am J Obstet Gynecol 104:909914 Nelson KB, Ellenburg JH 1986 Antecedents of cerebral palsy. N Engl J Med 315:81-86 Pharoah P, Connelly K, Hetzel B, Ekins R 1981 Maternal thyroid function and motor competence in the child. Dev Med Child Neurol 23:76-82 Escobar del Rey F, Pastor R, Mallot J, Morreale de Escobar G 1986 Effects of maternal iodine deficiency on the L-thyroxine and 3,5,3'-triiodo-L-thyronine contents of rat embryonic tissue before and after onset of fetal thyroid function. Endocrinology 118:12591265 Porterfield SP, Hendrich CE 1975 The effect of maternal hypothyriodism on maternal and fetal tissue glucose- 1-14C incorporation in rats. Horm Res 6:236-246 Hendrich CE, Jackson WJ, Porterfield SP 1984 Behavioral testing of progenies of Tx (hypothyroid) and growth hormone-treated rats: animal model for mental retardation. Neuroendocrinology 38:429-437 Bakke JL, Lawrence NL, Robinson S, Bennett J 1975 Endocrine

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studies of the untreated progeny of thyroidectomized rats. Pediatr Res 9:742-748 Porterfield SP, Hendrich CE 1982 Brain and liver DNA and RNA in the progeny of hypothyroid and GH-treated hypothyroid rats. Endocrinology 111:408-411 Porterfield SP, Hendrich CE 1982 Ganglioside and galactolipid accumulation in the progeny of hypothyroid and hypothyroid growth hormone treated pregnant rats. Horm Metab Res 14:225226 Karlsson I, Svennerholm L 1978 Biochemical development of rat forebrains in severe protein and essential fatty acid deficiencies. J Neurochem 31:657-662 Porterfield SP, Whittle E, Hendrich CE 1975 Hypoglycemia and glycogen deficits in fetuses of hypothyroid pregnant rats. Proc Soc Exp Biol Med 149:748-753 Porterfield SP, Hendrich CE 1987 Iodothyronine-5'-deiodinase activity in progenies of hypothyroid rats. Horm Metab Res 19:609612 Ruiz de Ona C, Morreale de Escobar G, Calvo R, Escobar del Rey R, Obregon MJ 1991 Thyroid hormones and 5'-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism. Endocrinology 128:422-432 Ruiz de Ona C, Obregon MJ, Escobar del Rey F, Morreale de Escobar G 1988 Development changes in rat brain 5'deiodinase and thyroid hormones during the fetal period. The effects of fetal hypo-thyroidism and maternal thyroid hormones. Pediatr Res 24:588-594 Hendrich CE, Wiedmeier VT, Porterfield SP 1982 Utilization of alanine by hypothyroid rats, their fetuses and progeny. Horm Metab Res 12:658-666 Hendrich CE, Ocasio-Torres W, Berdecia-Rodriguez J, Porterfield S, Brain and liver ribosomal protein synthesis and profiles in hypothyroid mothers and the their progenies. Program of the 62nd Annual Meeting of the American Thyroid Association, Washington, D.C., State, 1987, p 120 (Abstract 106) Narayanan CH, Narayanan Y 1985 Cell formation in the motor nucleus and mesencephalic nucleus of the trigeminal nerve of rats made hypothyroid by propylthiouracil. Exp Brain Res 59:257-266 Bonet B, Herrera E 1988 Different response to maternal hypothyroidism during the first and second half of gestation in the rat. Endocrinology 122:450-455 Bonet B, Herrera E 1991 Maternal hypothyroidism during the first half of gestation compromises normal catabolic adaptations of late gestation in the rat. Endocrinology 129:210-216 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 Bernal J, Perez-Castillo A, Pans T, Ferreiro B 1985 Developmental patterns of thyroid hormones nuclear receptor. In: Kochupillai N, Karmarkar MG, Ramalingaswani V (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, pp 132-137 Bernal J, Pekonen F 1984 Ontogenesis of the nuclear 3,5,3'triiodothyronine receptor in the human fetal brain. Endocrinology 114:677-679 Ferreiro B, Bernal J, Goodyer CG, Branchard CL 1988 Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J Clin Endocrinol Metab 67:853-856 Bernal J, Perez-Castello A, Pans A, Pekonen F 1984 Ontogenesis of thyroid hormone receptor. In: Labrie L, Proulx L (eds) Endocrinology: International Congress Series 655. Exerpta Medica, Amsterdam, p 977 Mellstrom B, Naranjo JR, Santos A, Gonzalez AM, Bernal J 1991 Independent expression of the alpha and beta c-erbA genes in developing rat brain. Mol Endocrinol 5:1339-1350 Silva JE 1985 Thyroid hormone metabolism in the neonatal rat brain: effect of the thyroid status. In: Kochupillai N, Karmarkar MG, Ramaligaswami V (eds) Iodine Nutrition Thyroxine and Brain Development. Tata McGraw-Hill Publishing Co Ltd, New Dehli, pp 150-167

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