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 also of the intricate network of regulatory systems required for mature thyroid function as well. These include the development of the hypothalamus and pituitary glands, and, in addition, the coordinated maturation of mechanisms required for thyroid hormone transport, metabolism, and action. During fetal life circulating levels of thyroxine (T₄), and its active metabolite triiodothyronine (T₃), are low whereas the inactive metabolites reverse T₃ (rT₃) and T₃ sulfate are high. This pattern of metabolites is a consequence of both immaturity of the hypothalamic–pituitary–thyroid axis and coordinated adjustments in the deiodinase system that determine whether T₄ will be activated or inactivated. Despite the low serum T₃ concentration, the level of T₃ in vital organs such as brain is preserved, reflecting the importance of local conversion of T₄ to T₃. Maternal thyroid hormone, regulated by placental transport and metabolism, contributes to the early fetal thyroid hormone supply, particularly in the first half of gestation. The physiologic rationale for the maintenance of reduced circulating T₃ levels throughout fetal life is still unknown, but it has been suggested that its function may be to avoid tissue thermogenesis and potentiate the anabolic state of the rapidly growing fetus while at the same time permitting highly regulated, tissue-specific maturation in an orderly temporal sequence.

Postnatally, changes in thyroid hormone secretion and metabolism occur that permit the neonate to adapt to the changing demands of extrauterine life. Unique to the childhood years, thyroid hormone plays a critical role in the maturation of numerous target organs, including bone, brown adipose tissue (BAT), cochlea, retina, liver, lungs, and heart as well as brain. These maturational programs are precisely controlled and occur in developmentally regulated, tissue-specific windows of time. In this chapter, the intricate regulation of the development of the thyroid system will be reviewed and recent important insights into our understanding discussed.

Thyroid system ontogenesis can be divided into four phases: Embryogenesis, maturation of the hypothalamic–pituitary–thyroid system, maturation of thyroid hormone metabolism, and maturation of thyroid hormone transport and action. Postnatal thyroid function in infancy, childhood, and adolescence will also be described.

Thyroid hormone levels begin to rise in the human fetus concomitant with maturation of the hypothalamic–pituitary–thyroid system from midgestation through the neonatal period, with continuing adjustment of the thyroid-stimulating hormone (TSH)/free T₄ setpoint during childhood and adolescence. The maturation process involves ontogenesis of the hypothalamus and TRH secretion, pituitary thyrotroph TSH secretion, thyrotroph cell TRH receptors, hypothalamic and pituitary–thyroid hormone receptors, hypothalamic and pituitary iodothyronine monodeiodinase enzyme activities, and thyroid gland TSH receptors and postreceptor response systems (5,6,7) (Table 53.1). The net effect of these ongoing maturational events is reflected in the pattern of change in the prevailing serum TSH, free T₄ concentrations, and the TSH/free T₄ setpoint (Table 53.2) (8,9).

Figure 53.1 graphically displays maturation of hypothalamic–pituitary–thyroid function during the perinatal period as reflected by the TSH and T₄ concentrations versus gestation age. T₄, free T₄, and TSH concentrations in the fetus increase progressively during the latter half of gestation. The increasing T₄ level is due to estrogen-stimulated
hepatic synthesis of thyroxine-binding globulin (TBG). The increasing free T₄, which parallels total T₄, is due to increased T₄ secretion and saturation of TBG-binding sites.

The molecular events involved within thyroid system maturation are incompletely understood. The increasing free T₄ and TSH levels in the fetus (Fig. 53.1 and Table 53.2) presumably reflect an increasing TRH effect and increasing thyroidal TSH responsiveness (10). Hypothalamic TRH synthesis and secretion from the paraventricular nucleus (PVN) is regulated by T₃ with modulation by a variety of endogenous and exogenous factors including environmental temperature and metabolic rate mediated by neurotransmitters, including catecholamines, neuropeptide Y, and somatostatin (10). Type 2 iodothyronine deiodinase (D2) is not expressed in the PVN. Rather, T₃ is locally generated in glial tanycytes located in the floor and lateral walls of the third ventricle (11). It is postulated that cerebrospinal fluid T₄ is the substrate for the tanycyte D2–generated T₃ diffusing in a paracrine fashion to the PVN and other hypothalamic nuclei including the arcuate nucleus and median eminence. Pituitary TSH secretion is modulated by TRH and by T₃ generated by pituitary D2 which rapidly deiodinates T₄ to T₃. However, both serum T₃ and free T₄ appear to be required to suppress TRH mRNA in the PVN (11,12). T₄ modulation of pituitary D2 activity via ubiquitination and a high rate of D2 synthesis optimize the T₄ feedback mechanism for pituitary TSH secretion (11). The inactivating D3 enzyme also is a key regulator of the hypothalamic–pituitary control axis (12). D3 is expressed in neurons presumably to protect against superphysiologic levels of T₃. D3 knockout mice have elevated circulating thyroid hormone levels due to impaired T₃ clearance in the neonatal period and develop central hypothyroidism with defective TRH and TSH responsiveness at 2 to 3 weeks of postnatal age (12) (see Chapter 7).

At the level of the hypothalamus, T₃ binds to T₃ nuclear receptors suppressing prepro-TRH mRNA and TRH synthesis and secretion (13,14). In the pituitary gland T₃ binds to the T₃ nuclear beta receptor (TRβ2), which, in turn, binds to a thyroid negative response element on the promotor regions of TSHβ and common α subunit genes, inhibiting gene expression and decreasing TSH secretion (15). T₃ nuclear alpha receptors (TRα) may have a stimulating effect on TSH secretion; TRα receptor knockout in mice results in failure of TSH secretion in spite of decreased serum T₄ concentrations (15). Nuclear receptor cofactors are involved with the T₃ nuclear receptors in the mediation of thyroid hormone actions; a defective cofactor has been implicated in a kindred with thyroid hormone resistance (16). It is believed that thyroid hormones modulate TSH secretion via negative feedback while TRH maintains the free T₄ setpoint for TSH regulation.

In the developing rat during the period of thyroid system ontogenesis (16 to 18 days’ gestation through 20 to 21 days postnatal), there is a progressive simultaneous maturation of hypothalamic TRH secretion, TRH degrading enzymes, hypothalamic–pituitary TRH and T₃ receptors, and hypothalamic and pituitary iodothyronine monodeiodinase activities (17,18,19,20,21,22,23,24,25). At the end of the period of ontogenesis (17 to 18 days), the TSH receptor is first expressed and this is accompanied by significant thyroid growth and evidence of differentiated cell function (26). There is presumed analogous maturation of hypothalamic–pituitary functions in the human fetus during the comparable period of pituitary–thyroid axis development (the latter half of gestation and the early weeks of postnatal life) (5,7). Table 53.2 suggests major phases of thyroid axis control maturation (excluding the neonatal adaptation period): (a) The fetal phase of increasing free T₄ and increasing serum TSH levels, and (b) the postnatal phase of relatively stable free T₄ levels with decreasing serum TSH values (see later). Maturation of TRH secretion during the fetal phase with progressive reduction of TRH secretion during the postnatal phase would be the simplest hypothesis to explain the observed changes in serum TSH.

During transition from the fetal to the postnatal phase, there is a rapid fall in prevailing TSH concentration (Fig. 53.1, Table 53.2). Fetal serum TSH levels in the third trimester human fetus are relatively high, whereas equilibrated values after 1 to 2 weeks are significantly lower (Table 53.2). The mechanism(s) for the high fetal TSH values as well as the rapid postnatal fall in serum TSH in the absence of significant change in serum free T₄ concentrations is unclear. Decreased thyroidal TSH responsiveness or reduced TSH bioactivity probably contribute to the relatively higher fetal serum TSH levels and relatively high TSH/free T₄ ratio (Table 53.2) (27). Additionally, fetal serum TRH concentrations are relatively increased due to extrahypothalamic TRH production by placental and fetal gastrointestinal tissues and low serum levels of TRH degrading activity (18,19,20,21,28,29). Also fetal serum T₃ concentrations are low due to relatively low feto-placental iodothyronine monodeiodinase type D1 and high monodeiodinase type D3 activities and, by analogy with the fetal sheep, most T₄ in the fetus is rapidly converted to inactive sulfated analogs and rT₃ (30,31,32). Finally, the lower prevailing serum TSH concentrations postnatally are associated with increased TSH glycosylation and bioactivity, loss of placental TRH production, increased serum TRH degrading activity, increased T₃ production with decreased T₃ degradation, and decreased production of inactive thyroid hormone analogs (19,20,21,27,28,29,30,31) (Fig. 53.2). The earliest of these changes in term infants is the increase in serum levels of active T₃; other extrauterine adaptations are more delayed during the transition period and their relative contributions to the reduction in serum TSH concentrations are not clear.

The metabolism of thyroid hormones involves a progressive series of monodeiodinations mediated via three iodothyronine deiodinase enzymes, D1, D2, and D3 (11,32,33,34) (see Chapter 7). These enzymes act to remove an iodine atom from the outer (phenolic) ring or the inner (tyrosyl) ring of the tetraiodothyronine (T₄) molecule, respectively, activating or inactivating the hormone. D1 and D2 act as outer ring monodeiodinases deiodinating T₄ to active T₃. D1 also has inner ring deiodinase activity converting T₃ to inactive T₂. D3, with inner ring monodeiodinase activity, inactivates T₄ to rT₃ and T₃ to T₂. In most tissues, particularly liver and excluding brain and BAT, T₃ and rT₃, generated via T₄ monodeiodination, diffuse rapidly from tissue to interstitial fluid to plasma. In adults under normal circumstances, T₃ and rT₃ are produced at approximately similar rates. Significant amounts of T₃ and small amounts of rT₃ also are synthesized and released by the thyroid gland. Thus, the circulating levels of T₃ and rT₃ reflect both secretion and deiodination of T₄ in peripheral tissues. Seventy to ninety percent of
circulating T₃ is derived from peripheral conversion and 10% to 25% from the thyroid gland: Respective values for rT₃ are 96% to 98% and 2% to 4%. Progressive tissue monodeiodination reactions degrade T₃ and rT₃ to diiodo, monoiodo, and noniodinated thyronine (see Chapter 7).

In contrast to the relatively high T₃, low rT₃ environment of the adult, rT₃ levels are high and T₃ levels low in the fetus until 30 to 35 weeks of gestation (Figs. 53.1 and 53.2). Human fetal hepatic D1 activity levels are low throughout gestation, averaging 24% of adult levels, increasing in the perinatal period; D3 levels are high, 10 to 15 times adult levels, decreasing in the perinatal period (34,35,36). D2 activity in human fetal cerebral cortex increases between 13 and 20 weeks of gestation; cerebellar D2 activity increases after midgestation (37). Both D1 and D2 deiodinase species are thyroid hormone responsive. Hepatic D1 activity in the fetal sheep becomes thyroid hormone responsive (i.e., activity increases in response to T₄) during the final weeks of gestation; brain D2 is responsive (decreases in response to T₄) throughout the final third of gestation (38). The human fetal deiodinases respond similarly to T₄. In the hypothyroid human fetus D2 activity in brain tissue increases, and hepatic D1 is suppressed, shunting T₄ to the central nervous system and other tissues where it is preferentially deiodinated to T₃ by D2 (38). This provides a source of intracellular T₃ to those tissues most dependent on T₃ during fetal life including brain, pituitary, cochlea, BAT, and keratinocytes. Hepatic D1 enzyme activity (to provide increased serum T₃ levels) normally increases during the final weeks of gestation and during postnatal life. The predominance of D3 activity in the fetus, particularly in placenta, liver, and kidney, account for the increased circulating levels of inactive rT₃ (30,38,39,40,41). The persistence of high circulating rT₃ levels for several weeks in the premature infant indicates that the D3 activities expressed in nonplacental tissues also contribute importantly to thyroid hormone inactivation, maintaining the high fetal circulating rT₃ levels. The mixture of D2 and D3 activities in the placenta provides for the conversion of T₄ to T₃ and of T₄ and T₃ to rT₃ and T₂, respectively (30,34,35,38). D2 and D3 activities also have been identified in the uterus and D3 activity in the chorion and amnion (42).

Also in contrast to the adult, bioinactive sulfated iodothyronines are the major thyroid hormone metabolites circulating in the fetus (30,32,43,44) (Fig. 53.2). Sulfotransferase enzymes are present early in fetal life in placenta and in fetal liver, lungs, and brain. Sulfation of the phenolic hydroxyl group of the iodothyronine molecule appears to be a normal prerequisite step for monodeiodination (43). The sulfated iodothyronines are preferred substrates for D1 and concentrations are high in fetal serum in part because of low fetal D1 activity (30). Increased production of sulfated metabolites also contributes to high fetal serum levels. In the fetal sheep during the last third of gestation, the production rate of T₄ approximates 40 μg/kg/d, several fold greater than in adult animals (32). The production rates of inactive rT₃, and sulfated analogs T₄S, rT₃S, and T₃S, approximate 5, 10, 12, and 2 μg/kg/d, respectively, accounting for the large majority of T₄ metabolized daily in the euthyroid fetus (32). T₂S, T₁S, and triac sulfate also are significant fetal thyroid hormone metabolites (45,46). There is evidence that T₃S may have biologic activity (suppresses TSH) in vivo, suggesting that it can be desulfated by one or more tissue sulfatase enzymes (34). There is limited information regarding production and significance of acetic acid, glucuronide conjugated or the recently characterized thyronamine derivatives of the thyroid hormones in the fetus (47,48).