Publisher Summary This chapter discusses the maturation of hypothalamus and thyroid function It also discusses the maturation of the neurovascular communication system between the hypothalamus and pituitary in a newborn rat It is a progressive process continuing throughout the period of hypothalamic maturation By 17 days of gestation, the pituitary gland is surrounded by a capillary network and separated from the brain by a thin layer of mesenchyme and capillaries—this is referred to as the supra-tuberal plexus, or the secondary plexus of the portal system The chapter illustrates Triiodothyronine (T3) production rates in rats at different times after birth In the illustration, T3 production rates, per 100 body weight are plotted as mean and SEM The general pattern of ontogenesis of the hypothalamic-pituitarythyroid system in the human, sheep, and rat species is similar The timing of the several stages relative to parturition differs in the rat Human and sheep fetuses are delivered toward the end of the stage of development of neuroendocrine control and early in the period of maturation of tissue metabolic systems In contrast, the rat is delivered soon after completion of embryogenesis of the thyroid and pituitary glands early in stage II maturation of the hypothalamus

Ontogenesis of hypothalamic--pituitary--thyroid function and metabolism in man, sheep, and rat.

Preliminary report on a mass screening program for neonatal hypothyroidism.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

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Thyroid hormones in fetal growth and prepartum maturation.

Hormones have an important role in the control of fetal growth. They act on both tissue accretion and differentiation and enable a precise and orderly pattern of growth to occur during late gestation. In part, their actions on growth may be mediated by other growth factors such as the insulin-like growth factors (IGFs). Insulin stimulates fetal growth by increasing the mitotic drive and nutrient availability for tissue accretion. It has little effect on tissue differentiation. In contrast, the main effects of cortisol in utero are on tissue differentiation and maturation. Cortisol appears to act directly on the cells to alter gene transcription or post-translational processing of the gene products. Cortisol may also initiate the transition from the fetal to the adult modes of growth regulation by inducing the switch from IGF-II to IGF-I gene expression in the fetal liver. Thyroxine affects both tissue accretion and differentiation in the fetus by a combination of metabolic and non-metabolic mechanisms. Pituitary growth hormone, on the other hand, appears to have little part in the control of fetal growth, unlike its role postnatally. Fetal hormones, therefore, promote growth and development in utero by altering both the metabolism and gene expression of the fetal tissues. These hormonal actions ensure that fetal growth rate is commensurate with the nutrient supply and that prepartum maturation occurs in preparation for extrauterine life.

Endocrine regulation of fetal growth

FETAL DEVELOPMENT is dependent upon the presence of the placenta. This organ, which interfaces the maternal and fetal vascular systems, not only regulates the transfer of various substrates from mother to fetus but also produces polypeptide hormones important for the maintenance of pregnancy, the induction of labor (1) and the synthesis and metabolism of steroid hormones necessary for the development of the fetus (2). In this review we will examine the role of the placenta on various aspects of maternal and fetal thyroid function including the transport, synthesis, and metabolism of hormones and compounds related to thyroid function. Transport In this section we will review the available information on the transport of thyroid and related hormones and compounds known to affect thyroid function. The role of the placenta in the transport of the iodothyronines has been studied in many species. In the rat, Hoskins et al. (3) demonstrated that the administration of large doses of thyroxine (T4) to prophylthiou...

The Placental Transport, Synthesis and Metabolism of Hormones and Drugs which Affect Thyroid Function*

Extract: Thyroidectomies were performed through a flank incision and uterotomy on five fetuses of 1–4-year-old Columbia and Columbia Suffolk date-bred ewes of 90–110 days gestation. The fetuses were killed 19–43 days post-thyroidectomy. Body and organ weights, limb roentgenograms, DNA, RNA, and protein concentrations of selected tissues, cerebral and cerebellar lipid concentrations, and cerebellar cerebroside fatty acid composition were measured and compared with similar measurements in control animals. In the thyroidectomized fetuses mean carcass and lung weights were significantly reduced and wool development was consistently delayed. Extremity x-rays showed a delay in the time of appearance and a decrease in the size of epiphyseal centers. The mean DNA concentration was low in muscle tissue; mean protein concentrations were reduced in cerebellum, heart, lung, thymus, and muscle tissues, while mean total lipid concentration was low in cerebral tissue; the percentage of 18-carbon fatty acids was significantly increased in cerebellar cerebrosides. These results indicate that thyroid hormone deficiency, present during the last trimester of gestation in the ovine fetus, impairs carcass and lung growth, delays bone and skin maturation, inhibits growth in cell size in heart, lung, thymus, and cerebral tissues, and delays myelination in the central nervous system (CNS). Speculation: The present results, considered with results of other investigations of the effects of thyroid hormone deficiency in fetal and newborn mammals, indicate that hypothyroidism impairs somatic growth, delays bone growth and maturation, delays cell growth and replication in the CNS, and inhibits CNS myelination. The critical period for these effects varies in different species. In the rat this period is postnatal, whereas in the sheep it extends into the third trimester of pregnancy. During pregnancy, carcass growth, bone maturation, and lung maturation are most affected in the sheep; CNS changes are minimal. In man fetal hypothyroidism may produce some delay in bone maturation but somatic growth retardation and signs and symptoms of hypothyroidism are not usually present at birth. Moreover, as in the sheep, any delay in CNS maturation probably is minimal in utero, since very early postnatal treatment minimizes mental retardation. Thus early diagnosis and treatment of hypothyroidism is necessary and consideration of the possibility of newborn screening would seem appropriate.

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Growth and development of the thyroidectomized ovine fetus.

Extract: Experiments were conducted to assess the changes in fetal and maternal iodothyronine kinetics in sheep after removal of the fetal thyroid gland early in the 3rd trimester. Uterotomy was performed at 90–125 days of gestational age; the fetal neck was isolated and a thyroidectomy performed. Indwelling exteriorized fetal carotid artery and maternal jugular vein catheters were inserted and dual 131I- and 125I-labeled iodothyronine kinetic studies were conducted in the mother and fetus, respectively, at 4–37 days post-thyroidectomy. Serum thyroxine (T4), triodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations were measured by radioimmunoassay (RIA). Before thyroidectomy the mean fetal serum T4 level was 12.2 μg/100 ml (nine animals); this value fell to a mean of 1.7 μg/100 ml 3 days postoperatively and to a mean of <0.7 μg/100 ml 5–6 days post-thyroidectomy. The mean fetal serum T3 level was <18 ng/100 ml before thyroidectomy and remained unmeasurable throughout the study. The mean maternal serum T4 and T3 concentrations were 8.9 μg/100 ml and 94 ng/100 ml before thyroidectomy and did not change significantly during the study period. Maternal T4 turnover (T4s) averaged 533 μg/24 hr (11.9 μg/kg/24 hr) after fetal thyroidectomy, whereas the fetal value was <4.9 μg/24 hr (<3.2 μkg/24 hr). Maternal T3 turnover (T3s) averaged 62 μg/24 hr (1.27 μg/24 hr) after fetal thyroidectomy; the fetal value was <2.26 μg/24 hr (<1.05 μg/kg/24 hr). These fetal values, and particularly the the T4 results, are much less than those in the euthyroid fetus ( < 1.45 and 41 μg/kg/24 hrfor T3 and T4). Placental transfer of butanol-extractable T4 and T3 radioactivity occurred in both the fetal-maternal (F-M) and maternal-fetal (M-F) directions; chromatographic studies revealed that the transferred radioactivity represented T4 or T3. The mean fractional rate constants for T4 transfer were 0.0009/hr−1 and 0.00003/hr−1 and for T3 transfer, 0.007/hr−1 and 0.002/hr−1 in the F-M and M-F directions. Estimated net transfer of T4 was 0.6 μg and of T3, 0.7 μg/24 hr in the M-F direction. These amounts represent only about 7% of total T4 equivalent turnover (T4s + 4 × T3s) in euthyroid fetuses, and the high fetal serum TSH concentrations (300–1,500 μU/ml) indicated that the thyroidectomized fetuses were, in fact, hypothyroid. The present data indicate that fetal thyroidectomy in the sheep results in fetal hypothyroidism which persists in spite of large M-F gradients of T4 and T3 and a large F-M gradient of TSH. The results further substantiate the autonomy of the fetal pituitary-thyroid system; TSH and thyroid hormones do not cross the placenta in significant quantities even after fetal thyroidectomy. Speculation: The present results suggest that the athyroid fetus probably develops in utero in the absence of significant quanities of thyroid hormones. The fact that growth retardation is not observed at birth in the athyroid human fetus suggests that fetal somatic growth may not be thyroid hormone dependent. The high rate of T4s in the euthyroid fetus may be important to development of fetal brain and of bone near term.

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K Omori

Papers

Growth and development of the thyroidectomized ovine fetus.

The effect of fetal thyroidectomy on thyroid hormone metabolism in maternal and fetal sheep.