A J FORHEAD and A L FOWDEN Thyroid hormones and fetal 221:3 R87–R103 Review development Thyroid hormones in fetal growth and prepartum maturation A J Forhead1,2 and A L Fowden1 Correspondence should be addressed 1Department of Physiology, Development and Neuroscience, University of Cambridge, Physiology Building, to A L Fowden Downing Street, Cambridge CB2 3EG, UK Email 2Department of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK [email protected] Abstract The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal Key Words growth and development of the fetus. Their bioavailability in utero depends on " thyroid hormones development of the fetal hypothalamic–pituitary–thyroid gland axis and the abundance " intrauterine growth of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive " maturation hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and " neonatal adaptation 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 Journal of Endocrinology 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. Journal of Endocrinology (2014) 221, R87–R103 Introduction The thyroid hormones, thyroxine (T4) and triiodothy- environment in utero (Fowden & Forhead 2009, 2013). ronine (T3), are detectable in the fetal circulation from early Deficiency of thyroid hormones during intrauterine in gestation and have important developmental, meta- development impairs growth of the fetus and compro- bolic, and maturational effects in the fetus in all species mises its adaptation to extrauterine life (Fowden et al. studied to date including human infants. Their bioavail- 1998, Hillman et al. 2012, Sferruzzi-Perri et al. 2013). ability in fetal plasma and tissues is regulated develop- Conversely, fetal administration of thyroid hormones can mentally and also varies with species, gestational age, promote tissue differentiation and activation of many of availability of nutrients and oxygen, and the endocrine the physiological processes that have little or no function http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0025 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 07:49:04PM via free access Review A J FORHEAD and A L FOWDEN Thyroid hormones and fetal 221:3 R88 development before birth but which are essential for neonatal survival pituitary–thyroid axis and production of T4 and T3, (Fowden et al. 1998). This review examines the develop- ii) the peripheral conversion of T4 to more biologically mental control of fetal T4 and T3 bioavailability and active T3 or to inactive metabolites to vary circulating and discusses the role of these hormones in fetal growth and tissue-specific concentrations, and iii) the uptake of development with particular emphasis on the maturation thyroid hormones into target tissues and activation of of somatic tissues essential for survival immediately at cellular processes by binding to thyroid hormone birth. The important role of thyroid hormones in brain receptors (TRs; Fig. 1). Before birth, all of these factors development is not considered here as this has been show developmental and tissue-specific regulation. In reviewed extensively in recent years (Horn & Heuer 2010, addition, placental transfer of thyroid hormones from Patel et al. 2011, Puig-Domingo & Vila 2013, Stenzel & the mother can contribute to the concentration of thyroid Huttner 2013). hormones in the fetal circulation, depending on the species and placental type (Fig. 1). Bioavailability of thyroid hormones before birth Activity of the fetal hypothalamic–pituitary–thyroid axis In fetal and adult animals, the bioavailability of thyroid- The thyroid gland originates as an outgrowth from the stimulating hormone (TSH) and the two biologically developing pharyngeal floor in the early embryo and active thyroid hormones, T4 and T3, is determined by undergoes three main stages of growth and differen- several factors: i) the activity of the hypothalamic– tiation: pre-colloid, colloid, and follicular (Brown 2004, Mother Placenta Fetus – I– from diet Transport Hypothalamus + Na TRH I– – – – Hypothalamus I Anterior pituitary TRH Sodium–iodide symporter TSH Anterior pituitary Thyroid hormone transporters Thyroid Journal of Endocrinology – TSH MCT8, MCT10 LAT1, LAT2 Thyroid T4 and T3 OATP1A2, and OATP4A1 Target tissues T4 and T3 Metabolism Transporters: MCT8, MCT10 D2 and D3 LAT1, LAT2 → Metabolism T4 T3 OATP → T4 rT3 → T3 T2 Metabolism: T4S T4 D1, D2 D3 Sulfotransferase rT3S rT3 T3 T3S Sulfatase D1, D2 D3 T2 T2S Receptors: TRα and TRβ Figure 1 Schematic diagram showing the factors affecting the bioavailability of D1, D2, and D3, deiodinases; OATP, organic anion transporters; LAT1 and thyroid hormones in the fetus, placenta, and mother. TRH, thyrotropin- LAT2, L-type amino acid transporters 1 and 2; MCT8 and MCT10, releasing hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; monocarboxylate transporters 8 and 10. T3, triiodothyronine; rT3, reverse T3;T2, diiodothyronine; S, sulfated; http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0025 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 07:49:04PM via free access Review A J FORHEAD and A L FOWDEN Thyroid hormones and fetal 221:3 R89 development Santisteban 2013). The follicular structural development aspects of thyroid hormone activity in human, sheep, and of the thyroid gland coincides with the functional rats. These include development of the hypothalamic– development of the hypothalamic–pituitary–thyroid axis pituitary–thyroid axis, onset of thyroid hormone pro- and the secretion of thyroid hormones into the fetal duction, and expression of TRs. Overall, human and ovine circulation (Table 1). Hypothalamic neurones produce fetuses are similar in the timing, relative to gestational age, thyrotropin-releasing hormone (TRH), which stimulates of the structural development of the thyroid gland and the the thyrotropes of the anterior pituitary gland to secrete onset of thyroid hormone activity, while rodent species TSH. In turn, TSH acts on the thyroid gland to promote show relatively delayed maturation of thyroid hormone follicular growth and stimulate the synthesis and secretion bioavailability (Table 1; Fisher & Polk 1989, Polk 1995). of the thyroid hormones. In the human fetus sampled by From mid-gestation in human and ovine fetuses, the cordocentesis, serum concentrations of TSH and free and thyroid gland secretes T4 and T3 under the control of the total T4 increase from mid-gestation with an exponential hypothalamic–pituitary axis and the thyroid hormone rise in free T3 closer to term (Thorpe-Beeston et al. 1991a). axis is fully functional around the time of birth (Table 1). In fetal life, as in adult life, the thyroid hormones control In rats, however, maturation of thyroid hormone activity their own production by negative feedback effects on the continues up to 4 weeks of postnatal life (Table 1). hypothalamus and pituitary, at least by late gestation, although the axis continues to mature in sensitivity Metabolism of thyroid hormones in utero postnatally (Hopkins et al. 1975, Polk et al. 1991, Rakover et al. 1999, Hernandez et al. 2006). Normal production of The circulating concentrations of the thyroid hormones thyroid hormones by the fetal thyroid gland depends are controlled, not only by the output of the thyroid upon iodide uptake by the follicular cells of the gland and gland, but also by metabolism in peripheral tissues (Fig. 1). iodide is actively transported from the maternal circula- In the fetus, thyroid hormones can undergo deiodination tion across the placenta (Fig. 1). and sulfation to more or less active metabolites. The The pattern of thyroid gland development and metabolism of T4 into more genomically potent T3 or thyroid hormone activity is comparable in all mammals relatively bio-inactive reverse T3 (rT3) depends on the studied, but the timing of the developmental stages can activity of deiodinase enzymes, which are develop- vary between species. Table 1 compares the ontogeny of mentally regulated in specific tissues (Brent 2012,