Rosalind S. Brown
Stephen A. Huang
Delbert A. Fisher
The maturation of thyroid function in the human fetus is a complex process that involves the growth and development not only of the thyroid gland itself but of the intricate network of regulatory systems required for mature activity as well. These include the development of the hypothalamus and pituitary gland, and, in addition, the coordinated maturation of mechanisms required for thyroid hormone transport, metabolism, and action. In general, fetal thyroid hormone levels are low in the first half of human pregnancy. During this period the fetus is entirely dependent on maternal thyroid hormone, the supply of which is controlled by the placenta and circulating maternal levels. Fetal thyroid hormone secretion increases in the second half of pregnancy, coincident with hypothalamic–pituitary–thyroid maturation. Despite the low serum concentrations of fetal thyroid hormones early in pregnancy, triiodothyronine (T3) levels are well maintained in critical target tissues such as the fetal brain due to coordinate adjustments in the deiodinase system. Unique to the childhood years, thyroid hormone plays a critical role in the maturation of numerous target organs, including bone, brown adipose tissue, cochlea, retina, liver, lung, and heart, as well as brain. These maturational programs are precisely controlled and occur in developmental, regulated, tissue-specific windows of time. In this chapter, the intricate regulation of thyroid system development will be reviewed and recent important insights in our understanding discussed.
Much of our information about thyroid system development has derived from studies in two animal models, fetal-neonatal rodents and fetal sheep. Although the events of thyroid development are roughly comparable in rodents, sheep, and humans, important differences exist in both the structure of the placenta and the timing of development. In newborn rats, thyroid system development at birth (21 days) is relatively immature and is equivalent to the early third trimester human fetus. Therefore, it is possible to study much of the thyroid system development in the neonatal period in the absence of the placenta. Sheep fetuses on the other hand have more mature thyroid development at birth and provides a model for intrauterine human thyroid development. The timing of thyroid hormone–dependent brain maturation relative to the intrauterine development also differs in the three species. In infant rats, from which much of our detailed information has been obtained, the major period of thyroid dependency of brain maturation extends from birth or slightly before to about 40 days of postnatal age. In sheep, thyroid-dependent brain maturation extends from 70 to 90 days of the 150-day gestation to several postnatal weeks. In human infants, the period of maximal thyroid-dependent brain development probably extends from midgestation to about 2 years of postnatal age. Recently, however, evidence has been provided in both rodents and humans to suggest that thyroid hormone may play an important role in fetal brain development much earlier than was appreciated previously and that this period might extend prior to the onset of fetal thyroid hormone production.
THYROID SYSTEM ONTOGENESIS
Hypothalamic–Pituitary Embryogenesis
The first trimester of human pregnancy is characterized by embryogenesis of the thyroid gland, hypothalamus, and pituitary. Glandular development is dependent on an orderly cascade of transcription factors and signaling molecules that determine organogenesis and cell determination and specification. Transcription factors involved in early human fetal forebrain and hypothalamic development include sonic hedgehog (SHH) and ZIC-2 (a homologue of the odd-paired gene). These genes are first identified at about 3 weeks of gestation, when the hypothalamus starts to differentiate. Mutations of and have been identified in familial and sporadic holoprosencephaly (1,2). Another important homeobox gene is , mutations in which have been shown in siblings with septo-optic dysplasia involving midline brain defectsDrosophilaSHHZIC-2HESX-1 and pituitary hypoplasia (3). SF-1, and the LIM class homeodomain factors LHX-3 and LHX-4 also play a role (4), but current understanding of the interaction of these factors is limited (see Chapter 2).
Considerable information has been developed in rodents regarding transcription factor programming of pituitary embryogenesis (5). The Rathke's pouch homeobox and the pituitary homeobox gene () are early factors in a cascade of determinants, including , , , , and , and targeted disruption of these factors in mice leads to stillbirth or neonatal death (4). Thyroid transcription factor 1 () knockout leads to pituitary gland as well as thyroid gland aplasia. and , LIM-class homeodomain transcription factors, are also essential for normal pituitary embryogenesis. The terminal factors in the cascade are and , which program development and function of pituitary cells producing growth hormone (GH), prolactin, thyrotropin (TSH-β), and the growth hormone–releasing hormone (GHRH) receptor (4). Mutations in and have been described in patients with familial hypopituitarism (5).PTX-1TTF-1LHX-3LHX-4Prop-1Pit-1TTF-1LHX-3LHX-4Prop-1Pit-1Prop-1Pit-1
Anatomically, the pituitary gland develops from two anlages: an evagination of the floor of the primitive forebrain and a ventral pouch from the ectoderm of the primitive oral cavity. The latter, Rathke's pouch, is visible by 5 weeks, evolving to a morphologically mature pituitary gland by 14 weeks. The pituitary–portal blood vessels have begun to develop by this time, and maturation continues through 30 to 35 weeks' gestation. The hypothalamic nuclei, median eminence, and supraoptic tract are identifiable by 15 to 18 weeks, and significant concentrations of thyrotropin-releasing hormone (TRH) and dopamine are detectable at this time. The anterior pituitary hormones, including TSH, can be identified by immunoassay at 10 to 17 weeks, and concentrations increase progressively thereafter (see Chapter 2).
Thyroid Gland Embryogenesis
The thyroid gland is derived from fusion of a medial outpouching from the floor of the primitive pharynx, the precursor of the thyroxine (T4)-producing follicular cells, and bilateral evaginations of the fourth pharyngeal pouch, which give rise to the parafollicular, or calcitonin (C)-secreting cells (6). Analogous to pituitary gland development, commitment toward a thyroid-specific phenotype as well as the growth and descent of the thyroid anlage into the neck results from the coordinate action of multiple transcription factors, hormones, and growth factors. The approximate timing of molecular events controlling thyroid gland development in rats is summarized in Table 74.1. Three transcription factors, , , and , are expressed before or just after the first appearance of the thyroid diverticulum on fetal day 9.5 to 10 and appear to be of major importance not only in early thyroid embryogenesis but in thyroid-specific gene expression as well (7,8,9,10,11). , a homeodomain-containing transcription factor, is expressed in both follicular cells and C cells. Targeted disruption of the gene results in mice completely devoid of thyroid tissue (11). In contrast, , a paired domain-containing transcription factor, is expressed only in thyroid follicular cell precursors and is involved in transcriptional regulation of the thyroglobulin and thyroid peroxidase genes but not the TSH receptor gene (10,12). The thyroid glands of mice lacking are reduced in size, lack follicles, and are composed almost exclusively of C cells. A specific set of genes ( and the paralogous gene ), members of a large family of genes that impart important patterning information in embryogenesis, appear to be important in the expression of and , respectively (13,14). Similarly, , a member of the same family of genes as , is expressed prior to in the pharyngeal floor and thyroid primordium and may play a role in regulation (15). It is of interest that both , , and are also expressed in a limited number of other cell types, suggesting that it is the specific combination of transcription factors and possibly non-DNA binding cofactors acting coordinately that determine the specific genotype of a cell. For example, as noted, is also expressed in the pituitary gland as well as the lungs, whereas is expressed in the kidney (see Chapter 2).TTF-1TTF-2PAX-8TTF-1TTF-1PAX-8PAX-8HOXHOX-A3HOX-B3PAX-8TTF-1NKX-2.5TTF-1TTF-1TTF-1TTF-1TTF-2PAX-8TTF-1PAX-8
TABLE 74.1. APPROXIMATE TIMING OF MOLECULAR EVENTS CONTROLLING THYROID GLAND DEVELOPMENT IN RATS
Fetal Age (Days)
Molecular Event
Development Concomitant
8.5–9.5
NKS-2.5, HOX-A3, and HOX-B3 genes expressed in primitive pharynx
9.5–10
TTF-1, TTF-2, and PAX-B genes expressed
Appearance of thyroid diverticulum
14–16a
TTF-2 expression decreases and disappears
14.5–15
—
Parathyroid glands join thyroid;migration completed
15–15.5
Tg, TPO, TSH receptor expressed
17–18
Tg, TPO, TSH receptor expression upregulated
Appearance of TSH in serum
Appearance of thyroid follicles, iodine uptake, iodide uptake, and thyroid hormonogensis
21
—
Delivery
aBy analogy with data in mice.
Tt, thyroglobulin;TPO, thyroid peroxidase;TSH, thyrotropin;TTF,
Thyroid descent to the anterior neck is complete by fetal day 14.5 to 15 in rats; thyroglobulin, thyroid peroxidase, and TSH receptor gene expression can be demonstrated as early as fetal day 15 to 15.5 (7,16). In view of the 5- to 5.5-day delay between the first appearance of , , and and thyroid-specific gene expression, additional factors must be involved. , a forkhead domain–containing binding protein, is down-regulated between fetal day 13 and fetal day 15 in mice (equivalent to fetal day 14 and 16 in rats), and it has been proposed that, in addition to its role in the commitment to a thyroid-specific phenotype, acts both to promote migration and repress thyroid-specific gene expression in thyroid follicular cell precursors (9). This interpretation is supported by findings in null mice, which develop one of two phenotypes; either the thyroid gland fails to develop, or a sublingual thyroid gland is formed, demonstrating evidence of thyroid differentiation, at least as indicated by thyroglobulin expression (17).TTF-1TTF-2PAX-8TTF-2TTF-2TTF-2
At fetal day 15, despite early evidence of thyroid-specific gene expression, the rat thyroid gland is difficult to distinguish from the surrounding structures, and neither iodine organification, thyroid hormonogenesis, nor evidence of a follicular structure is present. Thus, and are necessary but not sufficient for expression of the fully differentiated thyroid phenotype. On day 17 to 18, TSH receptor gene expression is dramatically up-regulated, and this is accompanied by significant growth and rapid development of both structural and functional characteristics, suggesting that the TSH receptor plays a role atTTF-1PAX-8 this later stage of development (18). Expression of both thyroglobulin and thyroid peroxidase messenger RNA (mRNA) increase, thyroid follicles develop, thyroid peroxidase enzyme function can be demonstrated, and there is evidence of thyroid hormonogenesis (18,19,20). In contrast, hyt/hyt mice, which have a loss-of-function (Pro556-Leu) mutation in the transmembrane domain of the TSH receptor, have severe hypothyroidism and hypoplastic but normally located thyroid glands with a poorly developed follicular structure (21). Similar findings have been described in infants born to mothers with potent TSH receptor blocking antibodies and in infants with loss of function mutations of the TSH receptor (22,23). Up-regulation of TSH receptor gene expression on fetal days 17 to 18 in rats is coincident with the first appearance of pituitary TSH in the fetal circulation and implies that, unlike in adults, the TSH receptor in the fetus may be upregulated by TSH (18,24). Following fetal days 17 to 18, there is continuing maturation of thyroid gland morphology and function.
Information regarding the early phases of human fetal thyroid embryogenesis is limited, but thyroid gland embryogenesis and descent are largely complete by 10 to 12 weeks' gestation. At this stage, tiny follicle precursors can be seen, iodine uptake can be identified, and thyroglobulin is present in the follicular spaces (25,26,27). Thyroid hormonogenesis is detected by 11 to 12 weeks, coincident with the appearance of TSH in the fetal circulation.
Maturation of the Thyroid System Control
Hypothalamic–Pituitary Axis and Hormone Transport
The key events in thyroid development are summarized in Figure 74.1. The secretion of TSH and thyroid hormones is minimal until midgestation (28,29). At this time (18–20 weeks of gestation), fetal thyroid gland iodine uptake and serum T4 concentrations begin to increase. The fetal serum TSH concentration progressively increases from a low value at 16 to 18 weeks, associated with progressive increases in serum total and free T4 concentrations between 20 weeks and term (28,29). Maturation of control of thyroid hormone secretion is superimposed on a progressive increase in fetal serum thyroxine-binding globulin (TBG) concentration caused by maturation of fetal hepatic TBG synthetic capacity. Pituitary TSH responsiveness to exogenous TRH is present early in the third trimester, and maturation of negative feedback control of pituitary TSH secretion develops progressively during the last half of gestation and the first 1 to 2 months of extrauterine life (28,30,31). Although immature, the fetal hypothalamic–pituitary system is capable of responding to hypothyroxinemia; congenital hypothyroidism in the 24-week fetus has been associated with a markedly increased serum TSH concentration (32).
FIGURE 74.1. Maturation of thyroid gland development and function during gestation. During the first half of gestation the fetus is dependent on maternal thyroxine (T4), the supply of which is regulated by placental deiodinase. Although first detected at 10 to 12 weeks, fetal T4 and free T4 concentrations do not begin to increase until 18 to 20 weeks, coincident with increasing hypothalamic-pituitary maturation. Serum levels of TRH and inactive T4 metabolites, such as reverse triiodothyronine (T3), are high in fetal life (not shown). (From Brown RS, Larsen R. Thyroid gland development and disease in infancy and childhood. In: DeGroot L, Hennemann G, eds. Thyroid . Accessed at disease managerhttp://thyroidmanager.org, accessed August 30, 2004.)
During the neonatal period, the serum free T4 concentration increases in response to an early neonatal TSH surge, and there is a marked increase in free T4concentration associated with a decline in TSH by 3 to 5 days (25,28,30) (Fig. 74.1). The free T4:TSH and free T3:TSH concentration ratios approximate adult values by 1 to 2 months of age (28). Thus, the human fetus matures from a state of combined primary and hypothalamic–pituitary hypothyroidism during the first trimester, through a period of hypothalamic hypothyroidism during the last half of gestation, to a state of mature function by 1 to 2 months of postnatal life.
Development of Thyroid Gland Responsiveness and Autonomy
The progressive increase in fetal serum free T4 concentrations during the last half of gestation appears to be due to both increasing fetal serum TSH and progressive maturation of thyroid follicular cell responsiveness to TSH (29,33). There are no data regarding the thyroid response to TSH for the developing human fetus. Direct data are available, however, from fetal sheep, in which there is a progressive increase in the responses of serum T4 and the serum T4:TSH ratio to exogenous TRH during the last trimester of pregnancy (34).
Thyroid gland maturation also includes maturation of thyroid autoregulation of iodine transport. The thyroid gland of adult mammals can modify iodine transport relative to dietary iodine intake and exclusive of variations in serum TSH. The developing mammalian thyroid gland lacks this autoregulatory mechanism and is thus susceptible to iodine-induced inhibition of thyroid hormone synthesis (35,36). The ability of the thyroid gland to defend against the thyroid-blocking effect of excessive iodide on thyroid hormone synthesis does not develop until after 36 to 40 weeks of gestation in the human fetus (35). Thus, premature infants under this age are at risk for the development of iodine-induced hypothyroidism.
Maturation of Thyroxine Metabolism
In adult humans, sequential monodeiodination, catalyzed by the iodothyronine deiodinase family of selenoenzymes, is the main pathway of thyroid hormone metabolism. As detailed in Chapter 7, removal of an iodine atom from the outer ring of T4 leads to substrate activation, a reaction catalyzed by types 1 (D1) and 2 (D2) deiodinase. Conversely, inner ring deiodination, catalyzed primarily by D3, leads to substrate inactivation. The three deiodinases share sequence homology around the active center, but different genes encode them and important differences exist with regard to their substrate affinity, tissue distribution, and sensitivity to inhibition by propylthiouracil. In the euthyroid state, approximately 80% of circulating T3 is derived from the outer ring deiodination of T4 in peripheral tissues (catalyzed by D1 and D2), and 80% of thyroid hormone is ultimately inactivated by inner ring deiodination (catalyzed by D3). In some tissues, such as the liver and kidney, most T3 is derived from plasma and only 25% of the intracellular T3 is generated from T4. In contrast, in the pituitary gland and cerebral cortex, local conversion of T4 to T3 plays a significantly more important role.
Compared with adult serum, fetal serum has low concentrations of free T4 and T3 and high concentrations of several inactive iodothyronine metabolites (rT3, T2, T3S, T4S) (37) (Fig. 74.2). Although the physiologic significance of the low serum levels of T3 is still unknown, it has been suggested that its function may be to avoid tissue thermogenesis and potentiate the anabolic state of the rapidly growing fetus. The low serum T3 concentration is due both to increased activity of the inactivating deiodinase (D3) as well as to the low expression of D1, the major activating deiodinase in adults. Animal studies have documented D3 in the uteroplacental unit as well as in multiple embryonic structures, including the liver, brain, gonads, lung, heart, intestine, and skin (38,39,40,41). Of interest is the recent finding that D3 expression is localized in areas of the neonatal rat brain involved in sexual differentiation (42,43). In humans, studies have shown, similarly, high levels of D3 activity or protein in the fetal liver, the cerebral cortex, and the epithelial structures of the embryonic lung, intestine, skin, and urinary tract (44,45,46,47). The possibility that this increased D3 activity may protect the developing embryo from T3 and T4 is supported by findings in mice with a targeted disruption in D3 (48). These D3-deficient mice are exposed to more maternal Tin utero3 and T4 levels and demonstrate significant growth retardation and perinatal mortality. Similarly, recent evidence suggests that the gene for D3 ( in mice, in humans) is expressed preferentially from the paternal side. Disruption in the imprinting status of results in abnormal thyroid hormone levels and may explain, in part, the phenotypic abnormalities in mice with uniparental disomy 12 and its human equivalent uniparental disomy 14 (49).Dio3DIO3Dio3
FIGURE 74.2. Differences in deiodinase activity in the maternal, placental, and fetal compartments. In the fetus, high levels of inactive thyroxine (T4) metabolites and of sulfated analogues are present. This occurs because of increased activity of the inactivating deiodinase, D3, in fetal life, coupled with immaturity of D1, the major activating deiodinase in the adult. The placenta also contains high D3 activity that serves to inactivate most of the maternal T4 presented to it. Nonetheless, significant maternal-fetal T4 does occur, particularly when T4 levels in the fetus are low. (From Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. 1994;331:1072–1078, with permission.)N Engl J Med
In contrast to D3, D2 is the major activating deiodinase expressed in the fetus. D2 is present in brain, pituitary, cochlea, brown adipose tissue, keratinocytes, and placenta. In rats, D2 activity in fetal brain is relatively low early in gestation and increases markedly during neonatal life to reach maximal levels at 2 to 3 weeks of life (38). The increase in D2 activity is coincident with an 18-fold increase of brain T3 content (50). In humans, both D2 and D3 activity are present in fetal brain as early as 7 to 8 weeks' gestation, indicating that the ability to convert T4 to T3 is present prior to the onset of fetal thyroid function (46). As in adults, the coordinated expression of these deiodinases throughout gestation determines the levels of the iodothyronines in fetal serum. Additionally, the tissue-specific expression of these enzymes allows the local concentration of T3 to vary from one structure or compartment compared with another. For example, compared with adults, the human fetal cerebral cortex has a higher content of T4 and T3 with similar rT3 content, despite the relatively low concentrations of T4 and T3 in fetal serum (45,51). This occurs because of the presence in fetal brain and pituitary of D2, the activity of which increases when levels of T4 are low. This represents an important level of prereceptor regulation of thyroid hormone action. In rodents, deiodinase activity in the fetal brain maintains local concentrations of in the normal range despite alternations in maternal thyroid status (52). A similar protective regulation in humans may explain the excellent neurologic outcome observed in infants with severe congenital hypothyroidism treated aggressively soon after birth.
Further evidence for the importance of the deiodinase system is the close temporal and spatial associations of the ontogeny of thyroid hormone metabolism and action. For example, in the mouse, D2 activity in the cochlea increases dramatically to reach a peak level at postnatal day 6, a few days prior to the onset of hearing (53). This is a critical period for the development of auditory function in rodents, and only thyroid hormone given to hypothyroid animals during the critical period prior to postnatal days 10 to 12 can rescue cochlear morphogenesis and auditory function (53). D2 expression is localized to connective tissue immediately adjacent to the sensory epithelium and spiral ganglion where thyroid hormone receptors (TRs) are found (53). Thus, it has been suggested that D2-containing cells in the connective tissue take up T4 from the circulation, convert T4 to T3, and then release T3 to the adjacent responsive cells. This provides an important degree of paracrine control of thyroid hormone action. A similar relationship is found in certain areas of the brain where D2 is expressed predominantly in glial cells, tanycytes (a specialized type of glial cells), and astrocytes, whereas TRs are found in the adjacent neurons and oligodendrocytes (42). Thus, T4, which enters the developing brain more readily than T3, is taken up from capillaries by glial cells, deiodinated to T3, and then transferred to neurons for action (42). In other areas of the brain, such as the pituitary gland, hippocampus, and caudate nucleus, D2 and TRs are coexpressed (42). As described previously for the cochlea, the development of D2 activity in the cerebral cortex in rodents is temporally associated with the period of maximum sensitivity to thyroid hormone action (54). Unlike D2, D3 is coexpressed with TRs in neurons, perhaps underlying the importance of protecting them from the effects of excess thyroid hormone (42).
In addition to deiodination, sulfation is another important pathway of thyroid hormone metabolism in the fetus (31). In adults, the sulfation of T4 and T3facilitates their degradation, because sulfated iodothyronines are excellent substrates for inner ring deiodination by D1. Sulfotransferase activity has been documented in human liver and kidney but, in adults, serum concentrations of sulfated iodothyronines are very low due to their rapid degradation by hepatic D1. The relatively high concentrations of these metabolites in fetal serum are presumably due to lower fetal hepatic D1 activity or decreased transport of T4and T3 into fetal hepatocytes. Sulfation is reversible and, in settings where sulfated iodothyronines are not rapidly cleared, these conjugated thyroid hormones may serve as a local reserve of active hormone in tissues containing sulfatase enzymes (55).
Throughout pregnancy, the programmed expression of deiodinases permits the maternal and fetal thyroid axes to function relatively independently. Birth signals a rapid transition to adult thyroid hormone metabolism. In chickens, hatching is characterized by a rapid increase in serum T3 that occurs in conjunction with a rapid decrease in hepatic D3 activity (56,57). Human birth is also associated with a rapid postnatal decline in hepatic and placental D3 activity and increase in brown-adipocyte D2 activity as part of adaptive thermogenesis. Both the decline in hepatic D3 and maturation of hepatic D1 activity contribute to a surge in serum levels of T3 postnatally. Within a few weeks of life, serum T3 concentrations in the newborn approximates these found in the adult, suggesting that maturation of deiodinase expression is complete (58).
Ontogenesis of Thyroid Receptors and Thyroid Hormone Actions
Receptor Maturation
As described in Chapter 8, the action of thyroid hormone is mediated primarily by specific nuclear receptors that function as ligand-mediated transcription factors to stimulate or inhibit expression of target genes (42). The binding of T3 to thyroid hormone receptors (TRs) is at least 10 times higher than that of T4. In addition to the four classical TRs—TRα1, TRα2, TRβ1, and TRβ2—multiple other transcripts that encode protein products have been identified. The gene encoding the TRα subtype is located on chromosome 17, whereas the gene encoding the TRβ subtype is on chromosome 3; the respective isoforms (1 and 2) result from alternative splicing of the initial mRNA transcripts. TRα2 and other splice variants, such as TRvα2 and TRvα3, do not bind T3 and may inhibit the binding of the other TRs to DNA (dominant negative inhibition). The TRα gene also produces an orphan receptor, rev-erb aα, that plays a role in cerebellar development. TRs exist as monomers, homodimers, or heterodimers with other nuclear proteins such as retinoid X-receptors. The heterodimeric structure is the active form of the receptor. TR activity requires the interaction of numerous coactivators and corepressors. In the unliganded state, some TRs repress gene function (42).
Like the iodothyronine deiodinases discussed above, the various TRs are expressed developmentally and differentially in tissues. TRβ1 mRNA expression is particularly abundant in liver and kidney, but is also found in parts of the developing brain, hypothalamus, pituitary, ear, and heart. In contrast, TRβ2 mRNA expression is much more restricted, the highest concentration being found in the pituitary gland. TRα1 and TRα2 are widely distributed among tissues (42).
The temporal sequence of thyroid hormone-mediated effects on maturation is developmentally regulated and occurs during a critical window of time. Although thyroid hormone–dependent pituitary, brain, and bone development occur early, other effects, such as those on liver, brown adipose tissue, lung, and heart, are detected only later in gestation. In rats, receptors can be detected in brain by binding assay as early as 13.5 to 14 days postconception, prior to the onset of fetal thyroid function. The concentration is low initially but increases subsequently, to reach a maximum level on postnatal day 6, accompanied by increased hormone occupancy. The TRα1 isoform is the predominant variant in fetal rat brain, and TRα1 mRNA is detected as early as embryonic days 11.5 to 12.5. Expression of the TRβ1 isoform, first detected at the time of birth, increases dramatically; there is a 40-fold higher concentration in the early postnatal period, with maximal level at postnatal day 10. The increase in TRβ1 mRNA is coincident with the neonatal surge in serum T3 and a postnatal increase in TR binding capacity. In contrast to the pituitary, hepatic nuclear T3 receptors mature during the first 3 to 5 weeks of extrauterine life, a period equivalent to the last trimester and early postnatal period of human fetal development (59,60,61). Other thyroid hormone effects, such as those on thermogenesis, hepatic enzyme activities, growth hormone metabolism, and growth factor metabolism [insulin-like growth factors (IGFs), nerve growth factor, epidermal growth factor] appear during the first 4 weeks postnatally. In sheep, the pattern of thyroid ontogenesis is comparable with that in rats and humans; in this species, however, most of the events of thyroid maturation occur (41).in utero
Receptor ontogeny in the human fetus recapitulates the situation in rodents and sheep. Both the T3 receptor, measured by binding assay, and the ligand T3, presumably of maternal origin, have been detected in fetal brain as early as 10 weeks' gestation, with a 10-fold increase in receptor abundance at 16 to 18 weeks (42). Using more sensitive methods, TR α1, TRα2, and TRβ1 isoforms have been detected at both the mRNA and protein level even earlier, at 8 weeks' gestation (46). In humans, like in rodents, TRα1 is the preponderant isoform early in gestation. Liver, heart, and lung receptor binding, on the other hand, are only identified at 16 to 18 weeks (62).
Ontogenesis of Thyroid Hormone Action
Thyroid Hormone–Mediated Brain Maturation
Of the multiple actions of thyroid hormone, none is more critical than the effect on brain development, as demonstrated by the severe, irreversible mental retardation and deafness characteristic of patients with untreated congenital hypothyroidism. In the brain, thyroid hormone mediates the maturation of a diverse array of processes that follow a precise developmental program and lead to the establishment of neural circuits essential for normal central nervous system development. Several excellent recent reviews of this topic are available (42,43,63). Cerebral histogenesis and cell migration, beginning prior to the onset of fetal thyroid hormone production, are the first processes to occur (Fig. 74.3). Once these neurons have migrated to their final destination, multiple events take place, manifested in rodents during the first 2 to 3 weeks of postnatal life (equivalent to the last trimester of human pregnancy and the first few months postnatally). Neurons begin to differentiate, form dendritic processes, and develop synapses. Cerebellar and hippocampal granule cells proliferate, migrate, and differentiate, and Purkinje cells develop their characteristic dendritic tree. Myelin-forming oligodendroglia proliferate, migrate, and mature, and axonal myelination is initiated. Cochlear and retinal maturation and gliogenesis are additional processes that occur in this later phase of brain development (53,63,64,65).
FIGURE 74.3. Comparative central nervous system ontogenesis in rats and humans. In both species, cerebral neurogenesis and cell migration occur . In rats, cerebellar maturation, neurite outgrowth, synaptogenesis, gliogenesis, and myelinogenesis are largely postnatal events. In humans, this period begins at 6 months' gestation and extends to 1 to 2 years of postnatal life. During much of rat fetal development and the first half of human gestation, the fetus is dependent on maternal thyroid hormones. (Modified from Porterfield HP, Hendrick CE. The role of thyroid hormones in prenatal and neonatal neurological development—current perspectives. 1993; 14:94, with permission.)in uteroin uteroEndocr Rev
Thyroid hormones provide the induction signal for the differentiation and maturation programs. In some cases, the absence of thyroid hormone appears to delay the timing rather than eliminate critical morphologic events or gene products, resulting in disorganization of intercellular communication. However, the molecular mechanisms by which this occurs are only now beginning to be understood. Consistent with a nuclear receptor mode of action, thyroid hormone stimulates numerous developmentally regulated genes, including genes for myelin, neurotrophins and their receptors, cytoskeletal components, transcription factors, extracellular matrix proteins and adhesion molecules, intracellular signaling molecules, and mitochondrial and cerebellar genes. In some cases these genes appear to be direct targets of thyroid hormone action; thyroid hormone response elements can be detected in the DNA regulatory region, or the genes are stimulated in cell culture. In other cases, thyroid hormone control may occur secondarily as a consequence of effects on terminal differentiation. In addition, thyroid hormone regulates some genes at the level of mRNA stability or mRNA splicing.
One of the unexplained paradoxes has been the surprising lack of developmental abnormalities in mice lacking TRα1, TRβ, or both, in contrast to the severe abnormalities in hypothyroid animals (66). Emerging evidence suggests that the reason for the abnormal brain development observed after thyroid hormone deficiency but not TR deficiency is transcriptional repression or abnormal regulation by the unliganded TR (42,43). For example, when mice lacking the TRα1 receptor were made hypothyroid, no effects on cerebellar development were seen, contrary to findings in wild-type animals (67). Analogous results were obtained with euthyroid mice containing a knock-in TR mutation designed to inhibit T3 binding but leave corepressor binding functions intact (68). As expected, these mice developed severe neurologic abnormalities. It is likely that the complexity of maturational control of thyroid hormone action involves developmental regulation of myriad factors that affect TR activity. These factors include corepressors and coactivators as well as transcription factors that compete with TRs for thyroid hormone response elements (TREs) on target genes, providing further levels of modulation (68).
There is also some evidence that the action of T4 on the developing CNS involves, in part, a nonnuclear mechanism. The work of Farwell et al has shown that T4-regulated actin polymerization plays an integral role in the regulation of deiodinase activity, and he and his colleagues have proposed that the action of T4on the actin cytoskeleton might be important in cellular migration, neurite outgrowth, and dendritic spine formation (69,70).
Thyroid Hormone–Mediated Growth
Thyroid hormones are critical for the normal growth and development of bone, as evidenced by the striking growth retardation, decreased growth velocity, and delayed ossification of the epiphyseal growth plate characteristic of long-standing, hypothyroidism in infancy and childhood. This growth-stimulatory actions of thyroid hormones occur in the context of a complex interplay of genetic, hormonal, and growth factor effects that are thyroid hormone independent (71,72). Thyroid hormone–mediated bone maturation involves both a direct and indirect action, the latter mediated by regulation of growth hormone gene expression and the IGF system (73). At a direct level, T3 regulates endochondral ossification and controls chondrocyte differentiation in the growth plate both and (74,75). Both osteoblasts and growth plate chondrocytes express TRs, and several Tin vitroin vivo3-specific target genes have been identified in bone (66). T3 also stimulates closure of the skull sutures , the basis for the enlarged anterior and posterior fontanelles characteristic of infants with congenital hypothyroidism (76). Complete deletion of TR b does not cause growth or bone abnormalities, whereas mutant TRα mice exhibit growth retardation, poor bone mineralization, and an immature, disorganized growth plate, suggesting that the action of thyroid hormone on bone is mediated primarily by TRα gene products (66). However, the growth retardation in TRαβ double knockout mice is more severe than that seen in mice with a targeted disruption of TR alone, implying that some important growth-promoting actions are performed by TRβ (66). The growth retardation in hypothyroid mice is more severe than that in TRαβ double knockout mice, consistent with the effect of the unliganded receptor in mediating the deleterious effects of thyroid hormone deficiency (66).in vivo
Thyroid Hormone–Mediated Brown-Fat Thermogenesis
A third important action of thyroid hormone is on the development of nonshivering thermogenesis, a metabolic change of profound importance to the neonate as it transitions from fetal to neonatal life. The ability of human infants and selected other homeothermic newborn mammals to maintain body temperature in the immediate extrauterine environment depends on the presence and function of brown adipose tissue (BAT), the cells of which have high concentrations of mitochondria (77,78,79) (see Chapters 38 and 60). The oxidative degradation of substrate, predominantly lipid, in BAT mitochondria as in other mitochondria provides a nicotinamide dehydrogenase–linked supply of electrons to coenzyme Q (ubiquinone) and to the cytochrome system. This respiratory chain maintains a proton gradient across the mitochondrial membrane that provides for the phosphorylation of nucleotides and storage of energy as adenosine triphosphate (79). Mitochondria contain a unique 32,000 molecular weight protein (uncoupling protein, UCP1, or thermogenin) on the inner membrane. UCP1 catalyzes the uncoupling of oxidative phosphorylation by dissipating the proton gradient created by the respiratory chain, resulting in energy dissipation as heat (80,81).
Cold-induced, nonshivering adaptive thermogenesis depends on the synergistic stimulation of UCP1 gene transcription by catecholamines and thyroid hormones. There is one functional cyclic adenosine monophosphate (cyclic AMP) response element (CRE) and two thyroid hormone response elements (TREs) in the UCP1 gene promoter. In rodents, the normal response of UCP1 to cold is blunted in hypothyroidism and requires the complete saturation of BAT TRs for an effect. Normalizing the UCP1 response of hypothyroid rats with exogenous T3 requires doses that cause systemic thyrotoxicosis, whereas the same results can be achieved with only physiologic replacement doses of T4 (82,83,84). This thermogenic response in T4-treated hypothyroid rats is due to the local conversion of T4 to T3 in BAT by D2, and can be blocked by the addition of the deiodinase inhibitor iopanoic acid (85,86). Experiments performed with D2 knockout mice have provided further direct evidence that D2 is required for the normal thermogenic response to cold stress. In the Dio2–/–knockout mice, cold exposure leads to hypothermia due to impaired BAT thermogenesis despite normal serum T3 concentrations and normal basal mitochondrial concentrations of UCP1. The hypothyroid-like abnormalities of the Dio2–/–knockout mice are completely reversed by the administration of T3 (87). The volume and functional activity of BAT, including D2 activity and UCP levels, increase progressively with fetal age so that BAT thermogenic activity is maximal in the perinatal period. As the human infant grows, shivering becomes the most important involuntary mechanism of cold-induced adaptive thermogenesis, and the anatomic distribution of BAT becomes restricted to the axillary, deep cervical, and perirenal adipose deposits (88).
Role of the Placenta
The placenta plays a vital role in fetal thyroid development and function by serving as an important site of thyroid hormone metabolism, by regulating the passage of substances from the maternal to the fetal circulation, and by synthesizing hormones that affect both maternal and fetal thyroid status (89). Much of our information has been derived from studies in rodents and sheep, but important differences exist in the structure of the placenta in humans and in these other species. Sheep have an epitheliochorial placenta in which the maternal and fetal circulations are separated by six tissue layers. Rats have a hemotrichorial placenta with four tissue layers separating the maternal and fetal circulation, whereas the human placenta is hemomonochorial with three tissue layers between the maternal and fetal circulations. Thus, differences in placental permeability to various substances, including drugs and hormones, might be expected among the three species.
Thyroid Hormone
Under normal circumstances, the placenta has only limited permeability to T4 and T3, and the fetal hypothalamic–pituitary–thyroid system develops relatively independent of maternal influence. Important species differences in the extent of maternal-fetal T
4 transfer exist, the order being rats > humans > sheep. The impermeability of the human placenta to thyroid hormone is due primarily to the high concentration of placental D3, which serves to inactivate most of the thyroid hormone presented from the maternal or fetal circulation, thereby protecting embryonic structures from the temporally inappropriate action of thyroid hormone (47). Immunostaining localizes D3 to the syncytiotrophoblast and cytotrophoblast layers of the placental membrane as well as to the fetal endothelium of the chorionic villi. Strong staining is also seen in the maternal decidua of human placentas and in the amniotic membranes. The iodide released serves to provide a continuing source of iodide for fetal thyroid hormone synthesis.
Human placental deiodination is a dynamic process, and activity varies throughout gestation. Specific activity is highest in the first trimester and then decreases as the pregnancy progresses. Although specific activity is decreased, total placental D3 activity is increased at term due to the concurrent increase in placental size. D2, which catalyzes the outer ring deiodination of T4 to T3, is also detectable in human placenta. However, placental D2 activity is approximately 200-fold lower than D3 activity throughout pregnancy, suggesting negligible contribution to the modulation of transplacental thyroid hormone transfer (90).
Recently, D2 and D3 activity has also been identified in the uterus (91,92,93). D3 activity is highest at the implantation site, but is also present in the endometrial glands of nonpregnant uteri. In rats, D3 activity at the implantation site is twice that in term placentas (94). In humans, the specific activity of endometrial homogenates from nonpregnant uteri exceeds that of term placenta (47). These data suggest that the uterus, like the placenta, also modulates the transfer of thyroid hormone to the fetus. Furthermore, the presence of high endometrial D3 activity in the nonpregnant state suggests that the local modulation of thyroid status is important at all stages of human reproduction, including implantation.
Importance of Maternal Thyroid Hormone
Despite the limited permeability of the placenta to T4, significant maternal-to-fetal transfer does occur, and current evidence suggests that this is particularly important when serum T4 concentrations in the fetus are low. For example, infants with the complete inability to synthesize T4 due to an inborn error of thyroid hormonogenesis nonetheless have cord T4 concentrations between 25% and 50% of normal (95). The results are similar in cord serum in infants with sporadic congenital athyreosis. This transplacental passage of maternal T4 (coupled with the coordinate adjustments in brain deiodinase activity discussed above) plays a critical role in minimizing the adverse effects of fetal hypothyroidism. Not only may it help to explain the normal or near-normal cognitive outcome of early-treated hypothyroid infants, but it also may provide a partial explanation for the relatively normal clinical appearance at birth of over 90% of infants with congenital hypothyroidism. In contrast, when both the mother and fetus are hypothyroid, such as in cases of iodine deficiency, potent TSH receptor blocking antibodies, or maternal-fetal PIT-1 deficiency, there is a significant impairment in neurointellectual development of the fetus despite the initiation of early and adequate postnatal thyroid replacement (96,97,98).
Recent evidence has suggested a role for maternal thyroid hormone on fetal brain maturation during the early stages of pregnancy as well. T4, presumably of maternal origin, has been detected in embryonic coelomic fluid as early as 6 weeks' gestation and in fetal brain as early as 10 weeks' gestation, prior to the onset of fetal thyroid function (99). Furthermore, both D2 and D3 activity as well as TR isoforms are present in human fetal brain from the middle of the first trimester (46,70,99,100), indicating that the machinery to convert T4 to T3 and to respond to T3 are present. In rodents, maternal hypothyroidism occurring prior to the onset of fetal thyroid function causes abnormal gene expression and aberrant cellular migration in the fetal cerebrum (101,102,103). Emerging evidence suggests that in humans, as well, both maternal hypothyroidism and even a low serum free T4 unaccompanied by a high serum TSH early in pregnancy may cause significant cognitive or motor delay in the offspring, although the magnitude of the deficit is not as great as when both fetal and maternal hypothyroidism are present (104,105,106). However, mild overt maternal hypothyroidismis relatively common conditions, occurring in as many as 2.5% of pregnant women in the United States (107). In addition, maternal hypothyroidism has been associated with other adverse effects, including an increased risk for fetal loss. For these reasons universal screening for hypothyroidism during or prior to pregnancy has been suggested (108).
Other Hormones and Factors
In contrast to T4 and T3, the placenta is freely permeable to TRH and to iodide, the latter being essential for fetal thyroid hormone synthesis. The placenta is also permeable to certain drugs, and to immunoglobulins of the immunoglobulin G (IgG) class. Thus, administration to the mother of excess iodide, or drugs, or the transplacental passage of TSH receptor antibodies from mothers with Graves' disease or primary hypothyroidism may have significant effects on fetal and neonatal thyroid function. The placenta is not permeable to thyroglobulin.
Although the placenta is permeable to TRH, the maternal serum TRH concentration is low, and most of the peptide transferred to the placenta is degraded. Thus, maternal serum contributes little, if any, TRH to the fetus. The placenta, however, is capable of TRH synthesis, and combined placental and fetal extrahypothalamic TRH production, the latter from the fetal pancreas and gastrointestinal tissues, leads to high concentrations of TRH in fetal serum (89, 109). The high fetal TRH concentration is maintained in part because of absent or low concentrations of TRH-degrading activity in fetal serum (109,110).
The placenta also produces large amounts of chorionic gonadotropin (hCG), which has inherent albeit low level TSH bioactivity. The circulating maternal levels peak at the end of the first trimester, stimulating a transient increase in serum free T4 and T3 concentrations in maternal serum and transiently suppressing maternal TSH secretion. These changes are minimal, however, and there is little influence on fetal thyroid function (111).
NEONATAL PERIOD
Term Infants
The changes in thyroid function associated with extrauterine adaptation of the term infant are shown in Figure 74.4 (25). Delivery of the term fetus into the extrauterine environment is associated with a transient, marked increase in serum TSH (the neonatal TSH surge) stimulated by neonatal cooling. This TSH surge, which peaks during the first 30 minutes at a secretory rate approximating 3 mU/L per minute, stimulates thyroidal release of T4 and T3 and a progressive increase in serum T4 and T3 concentrations during the first 24 to 36 hours of postnatal life (28,112). Umbilical cord occlusion triggers activation of BAT thermogenesis by removing placental inhibitors of BAT responsiveness to hormonal or neural stimuli (113). Both placental inhibitors and low fetal oxygen levels limit catecholamine release and BAT thermogenesis. One of the placental factors appears to be adenosine, which inhibits BAT thermogenesis, and the levels of which rapidly decrease after umbilical cord occlusion (113). BAT thermogenesis also is augmented by vaginal versus cesarean section delivery, as a result of higher catecholamine concentrations in infants born vaginally (114).in utero
FIGURE 74.4. Postnatal changes in the serum concentration of TSH, thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3) in term infants () versus premature infants () in the first week of life. Delivery is characterized by a postnatal surge in serum thyrotropin (TSH) that peaks at 30 minutes. This is followed by an increase in serum Tcontinuous linebroken line4 and T3 concentrations in the first few days that subsequently decrease. The serum concentrations of T4 and T3 rise postnatally because of maturation of glandular secretion and coordinate adjustments in deiodinase activity. In contrast, levels of rT3 decrease. Changes in premature infants are similar to those in term babies but are less marked. (From Fisher DA, Klein AH. Thyroid gland development and disorders of thyroid function in the newborn. 1981; 304:702–712, as modified by Brown RS, Larsen PR. Thyroid gland development and disease in infancy and childhood. In: DeGroot L, Hennemann G, eds. Accessed at N Engl J MedThyroid disease manager.www.thyroidmanager.org, August 30, 2001, with permission.)
In addition to the stimulation of BAT thermogenesis in newborn term infants, there is a dramatic and permanent increase in serum T4 and T3 concentrations (from 50 to 150 ng/dL) during the first 36 to 48 hours of postnatal life (28). This increase is due, at least in part, to increased secretion and to removal of the placenta from the fetal circulation, which reduces placental T3 deiodination, further increasing serum T3 concentrations (115). The progressive postnatal increase in serum T3 concentrations to levels characteristic of the extrauterine state is due largely to increased activity of hepatic D1 activity. This increased activity is stimulated in part by the maturational increase in free T4 concentrations.
After the first 1 to 2 hours, serum TSH concentrations decrease progressively, falling to permanent values characteristic of the extrauterine environment and significantly below cord serum concentrations. The mechanisms for this reduction in serum TSH concentration are not clear. The increased serum free T4 and free T3 concentrations play a role, but newborn serum TSH concentrations remain at the new, lower level even after the transient neonatal hyperthyroxinemic state has resolved. A resetting of the hypothalamic–pituitary set point for free T4 feedback control of TSH is involved, but maturative events are unclear. Umbilical cord cutting also removes the placental source of TRH (109). Whether this affects the TSH feedback control system is not known. Extrahypothalamic TRH could inhibit thyroid hormone suppression of TSH secretion, and reducing the prevailing intrauterine circulating extrahypothalamic TRH level tends to increase the FT4: TSH ratio.
Finally, transition to the extrauterine environment and umbilical cord cutting are associated with a progressive decrease in production and concentrations of inactive thyroid hormone analogues. These include rT3 and the sulfated metabolites T4S, T3S, rT3S, and T2S (115,116,117). This process occurs over several days to weeks and involves changes in activities of the deiodinase enzymes and perhaps tissue levels of sulfotransferase and sulfatase. The net effect is decreased production of bioinactive thyroid hormone analogues and increased production of T3.
Premature Infants
Preterm infants are delivered before full maturation of the hypothalamic–pituitary–thyroid system. They have qualitatively similar but quantitatively decreased changes in serum TSH and iodothyronine concentrations in the neonatal period (32,118,119). The serum TSH response to parturition is attenuated, and serum T4 concentrations remain below those in full-term infants during the first few weeks of life. An abrupt early neonatal (2–4 hours) increase in serum T3concentrations also occurs in premature infants, but the increments are smaller and serum T3 concentrations increase only slowly to the concentrations found in term infants. The timing of the decrease of the serum rT3 is similar to that in term infants (25,115,116).
Relative to term infants at birth, serum TBG and total T4 concentrations in premature infants are lower, tissue type I deiodinase activities and serum T3 levels are lower, TRH and free T4 concentrations are lower, bioinactive thyroid hormone analogue levels are higher, BAT thermogenic mechanisms are immature, and tissue thyroid hormone response systems are variably immature (118). The extent of these immaturities is related inversely to gestational age. All but the largest premature infants are relatively hypothyroxinemic, with serum levels of TBG, T4, and free T4 directly related to gestational age at birth. Serum free T4concentrations in the most immature (24- to 27-week) infants are twofold to threefold lower than values in term infants (120,121). This hypothyroxinemia, which is related to gestational age, is referred to as the hypothyroxinemia of prematurity. As indicated, it is characteristic of smaller low birth weight (LBW) infants (30–35 weeks' gestational age) and all very low birth weight (VLBW) infants (< 30 weeks' gestational age) (118,120,121). The mechanisms are not entirely clear and differ to some degree in LBW and VLBW infants. Low TBG concentrations, decreased T4 secretion largely resulting from inefficient thyroid gland synthesis, and decreased TSH secretion and action probably are involved (32,120,121,122,123).
Extrauterine hypothalamic–pituitary–thyroid adaptation in VLBW infants is more often compromised than in the more mature LBW infants. During the early neonatal period, the TSH surge and the early thyroidal response are limited and followed by a progressive decrease in serum T4 and free T4 concentrations, with a nadir at 1 to 2 weeks' postnatal age (120,124) (Fig. 74.5). The decrease in serum total T4 concentrations is due to a transient decrease in TBG, which appears to reflect neonatal morbidity (32, 123). Serum TSH levels usually do not increase in response to the transient hypothyroxinemia, and serum free T4levels return to cord serum values by 3 to 4 weeks (121,122,123).
FIGURE 74.5. Postnatal changes in serum T4 concentrations in very premature infants in the first 6 weeks of life. Unlike in older infants, no neonatal surge in thyroxine (T4) is seen. Rather, the T4 concentrations decrease in the first week of life to reach a nadir at 7 days. The extent of this decrease is related to the degree of prematurity. Values then normalize by 3 to 6 weeks of age. (From Mercado M, Yu VY, Francis I, et al. Thyroid function in very preterm infants. 1988;16:131–141, with permission.)Early Hum Dev
These very premature infants have a negative iodine balance during the early postnatal weeks, suggesting that they are unable to adapt to the extrauterine environment with augmentation of thyroidal iodine uptake and increased T4 secretion as do the older LBW infants (122). Serum thyroglobulin concentrations also are high, implying increased production of poorly iodinated thyroid hormone precursors or inefficient metabolism of thyroglobulin by the thyroid follicular cells, in either case a hyperactive, inefficient thyroid hormone synthetic process (122,123). Serum T3 concentrations also are low in VLBW infants as in older premature infants, but they fail to increase after T4 administration (125). Thus, conversion of T4 to T3 by type I deiodinase is minimal and associated with relatively low levels of enzyme activity, particularly in liver. Most of the circulating T3 in the very premature infant appears to be derived from thyroidal secretion (126).
Despite the reduced total T4 observed in some preterm babies, the TSH concentration is not significantly elevated in most of these infants. In some babies, transient elevations in TSH are seen, the finding of a TSH concentration greater than 40 mU/L being more frequent the greater the degree of prematurity. In one study, for example, the prevalence of a TSH concentration greater than 40 mU/L in VLBW (< 1.5 kg, i.e., very premature) infants was eightfold higher and in LBW (1.5–2.5 kg) infants twofold higher than in term infants (32). Whereas in some cases an elevated TSH concentration may reflect true primary hypothyroidism, in others this increase in TSH in preterm infants at several weeks of age may reflect the elevated TSH observed in adults who are recovering from severe illness. Such adults may have transient TSH elevations that are associated with still reduced serum T4 and T3 concentrations. These changes have been interpreted as reflecting a “reawakening” of the illness-induced suppression of the hypothalamic-pituitary axis. As the infant recovers from prematurity-associated illnesses such as respiratory distress syndrome (RDS), recovery of the illness-induced suppression of the hypothalamic-pituitary-thyroid axis also occur.
THYROID FUNCTION DURING INFANCY AND CHILDHOOD
During the prepubertal and pubertal periods of growth and development, there is progressive growth of the thyroid gland, a progressive increase in thyroglobulin and iodothyronine stores, and a progressive increase in production rate. The growth of the thyroid gland in residents of iodine-sufficient areas roughly parallels body growth. The gland volume, measured by ultrasonography, increases in size from about 1.0 g at birth to a mean of about 5 g at the age of 10 years (127). Average thyroid iodine content increases from 0.3 mg at birth to 16 mg in adolescents and adults. In areas of iodine deficiency, the average thyroid weight in newborn infants approximates 3 g, and iodine content may be as low as 0.04 µg. The iodide space increases progressively in volume. The relative size (liters per kilogram, expressed as percentage of body weight), however, decreases from about of 50% body weight at birth to 40% in 30 kg children (at about age 10 years). These values can be compared with the 33% body weight values in 65-kg adults.
Radioiodine uptake and clearance in children and adolescents vary with geographic location, diet, and iodine intake. Values have been reported both to decrease progressively with age during the first two decades and to remain relatively stable (128). This discrepancy is probably due largely to variations in iodine intake. The data showing a decrease with age were from areas of low iodine intake in Europe and Australia. A relatively high iodine intake could tend to mask differences in uptake with age.
Serum Thyroid Hormone Concentrations and Production Rates
During the first 20 years of life, serum total and free T4 and T3 concentrations decrease gradually (129,130,131). The decreases result largely from a decrease in serum TBG concentration that is progressive from early childhood through 15 to 16 years of age, when the mean serum TBG concentration is about the same as in adults. Reciprocal changes occur in serum transthyretin concentrations. These changes presumably reflect the effects of gonadal steroids, but other factors may be involved.
T4 turnover and production rate on a body weight basis (µg/kg per day) also decrease with age during the first two decades (132). Estimated T4 turnover or production rate values are 7 to 9 µg/kg per day in early infancy, 3 to 5 µg/kg per day at 1 to 3 years, 2 to 3 µg/kg per day at 3 to 9 years, and 1 µg/kg per day in adults.
The serum concentration of rT3 remains unchanged or increases slightly during childhood and adolescence (129). The serum free rT3 index (the product of the total rT3 and fractional T3 resin uptake) remains stable or increases slightly. Because circulating rT3 is derived predominantly from peripheral deiodination of T4, these observations and the fact that the mean calculated ratios of serum rT3/T4 and serum free rT3 index/free T4 index increase progressively with age suggest that the relative rate of T4 conversion to rT3 increases during childhood and adolescence (129). Direct measurements have not been made. The decreases with age in the ratios of serum T3/rT3 and free T3 index/free rT3 index suggest a progressive decrease in the relative conversion of T4 to T3 during the first 15 years of life.
The progressive decrease in serum free T4, T3 turnover, thyroglobulin, and thyroidal radioiodine uptake indicates a progressive relative decrease in thyroid function with age. The decreasing serum TSH concentration with age suggests that these decreases are mediated primarily by reduced TSH secretion. Whether this reflects decreased TRH secretion or non-TRH mechanisms is not clear. A progressive reduction in thyroid gland responsiveness to TSH also might be involved.
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