The role of the placenta in thyroid hormone delivery to the fetus

Abstract

The transplacental passage of thyroid hormones from the maternal circulation to the fetal circulation within the human hemochorial placenta is important for normal fetal development, particularly the development of the central nervous system. The role of maternal thyroid hormones is particularly important in the first half of pregnancy, before the onset of endogenous thyroid hormone production in the fetus. The human placenta regulates the quantity and composition of different forms of transported thyroid hormones to ensure that the requisite levels are present in the fetus for each stage of development. Transplacental thyroid hormone supply to the fetus is modulated by several factors, including the following proteins: plasma membrane transporters, which regulate the passage of thyroid hormones in and out of cells; iodothyronine deiodinases, which metabolize thyroid hormones; and proteins within trophoblast cells, which bind thyroid hormones. In pathological situations of either maternal or fetal thyroid hormone deficiency during pregnancy, the placenta seems to lack the full compensatory mechanisms necessary to optimize maternal–fetal transfer of thyroid hormones. Inadequate passage of thyroid hormones can lead to suboptimal fetal thyroid hormone levels, which might contribute to the neurodevelopmental delay associated with such conditions. Thus, maintaining normal maternal thyroid hormone status is likely to be the primary factor in ensuring adequate transplacental thyroid hormone passage and appropriate iodide supply to the fetus.

Key Points

  • The transplacental passage of thyroid hormones from the maternal circulation to the fetal circulation is important from the first trimester of pregnancy to ensure normal fetal development, particularly of the central nervous system

  • In normal pregnancy, transplacental thyroid hormone passage is modulated by plasma membrane thyroid hormone transporters, the metabolism of thyroid hormones by iodothyronine deiodinases, and the binding of thyroid hormones to several different proteins within placental trophoblast cells

  • In pathological pregnancies with either maternal or fetal thyroid hormone deficiency, the placenta lacks the full compensatory mechanisms necessary to optimize maternal–fetal transfer of thyroid hormones to achieve normal thyroid hormone levels in the fetus

  • Maintaining normal maternal thyroid hormone status is likely to be the primary factor in determining adequate transplacental thyroid hormone passage and appropriate iodide supply to the fetus

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Changes in concentrations of maternal and fetal thyroid hormones in the fetal circulation during human gestation.
Figure 2: The human placenta and fetus during early and late pregnancy.
Figure 3: Cross-sections of a placental terminal chorionic villous in early and late pregnancy.
Figure 4: The passage of T4 and T3 through placental trophoblasts from the maternal to the fetal circulation during pregnancy.

References

  1. 1

    Haddow JE et al. (1999) Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341: 549−555

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Pop VJ et al. (2003) Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 59: 282–288

    Article  Google Scholar 

  3. 3

    de Escobar GM et al. (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab 18: 225–248

    Article  PubMed  Google Scholar 

  4. 4

    Chan S. et al. (2002) Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex. Brain Res Dev Brain Res 138: 109–116

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Sinha AK et al. (1997) Thyroid hormone and brain maturation. In Recent Research Developments in Neuroendocrinology, 1–14 (Ed Hendrich CE). Trivandrum: India Research Signpost

    Google Scholar 

  6. 6

    Chan S et al. (2005) Maternal thyroid hormones and fetal brain development. Curr Opin Endocrinol Diabetes 12: 23–30

    CAS  Article  Google Scholar 

  7. 7

    Kilby MD et al. (2005) Thyroid hormone action in the placenta. Placenta 26: 105–113

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Barber KJ et al. (2005) The in vitro effects of triiodothyronine on epidermal growth factor-induced trophoblast function. J Clin Endocrinol Metab 90: 1655–1661

    CAS  Article  PubMed  Google Scholar 

  9. 9

    LaFranchi SH et al. (2005) Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid 15: 60–71

    Article  PubMed  Google Scholar 

  10. 10

    Casey BM et al. (2005) Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 105: 239–245

    Article  PubMed  Google Scholar 

  11. 11

    Negro R et al. (2007) Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function. J Endocrinol Invest 30: 3–8

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Grumbach MM and Werner SC (1956) Transfer of thyroid hormone across the human placenta at term. J Clin Endocrinol Metab 16: 1392–1395

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Vulsma T et al. (1989) Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321: 13–16

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Calvo RM et al. (2002) Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab 87: 1768–1777

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Costa A et al. (1991) Thyroid hormones in tissues from human embryos and fetuses. J Endocrinol Invest 14: 559–568

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Mandel SJ et al. (2005) Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 15: 44–53

    Article  PubMed  Google Scholar 

  17. 17

    Hume R et al. (2004) Human fetal and cord serum thyroid hormones: developmental trends and interrelationships. J Clin Endocrinol Metab 89: 4097–4103

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Bianco AC et al. (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23: 38–89

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Visser TJ (1996) Pathways of thyroid hormone metabolism. Acta Med Austriaca 23: 10–16

    CAS  PubMed  Google Scholar 

  20. 20

    Ferreiro B et al. (1988) Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J Clin Endocrinol Metab 67: 853–856

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Richard K et al. (1998) Ontogeny of iodothyronine deiodinases in human liver. J Clin Endocrinol Metab 83: 2868–2874

    CAS  PubMed  Google Scholar 

  22. 22

    Farwell AP et al. (2005) Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3′,5′-triiodothyronine. Brain Res Dev Brain Res 154: 121–135

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Farwell AP et al. (2006) Dynamic nongenomic actions of thyroid hormone in the developing rat brain. Endocrinology 147: 2567–2574

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Jauniaux E et al. (1991) In vivo investigations of the anatomy and the physiology of early human placental circulations. Ultrasound Obstet Gynecol 1: 435–445

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Schneider H (1991) Placental Transport Function. Reprod Fertil Dev 3: 345–353

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Chan S et al. (2003) Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies. J Clin Endocrinol Metab 88: 4488–4495

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Huang SA et al. (2003) Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab 88: 1384–1388

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Roti E et al. (1983) Inner ring deiodination of thyroxine and 3,5,3′-triiodothyronine by human fetal membranes. Am J Obstet Gynecol 147: 788–792

    CAS  Article  PubMed  Google Scholar 

  29. 29

    de Escobar GM et al. (1993) Effects of iodine deficiency on thyroid hormone metabolism and the brain in fetal rats: the role of the maternal transfer of thyroxin. Am J Clin Nutr 57 (Suppl 2): S280–S285

    Article  Google Scholar 

  30. 30

    Dowling AL et al. (2000) Acute changes in maternal thyroid hormone induce rapid and transient changes in gene expression in fetal rat brain. J Neurosci 20: 2255–2265

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Mitchell AM et al. (1992) Uptake of L-tri-iodothyronine by human cultured trophoblast cells. J Endocrinol 133: 483–486

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Friesema ECH et al. (2005) Membrane transporters for thyroid hormone. Curr Opin Endocrinol Diabetes 12: 371–380

    CAS  Article  Google Scholar 

  33. 33

    Friesema ECH et al. (2004) Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 364: 1435–1437

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Dumitrescu AM et al. (2004) A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74:168–175

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Heuer H et al. (2005) The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 146: 1701–1706

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Chan SY et al. (2006) Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. J Endocrinol 189: 465–471

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Kim DK et al. (2001) Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters. J Biol Chem 276: 17221–17228

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Ritchie JW and Taylor PM (2001) Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J 356: 719–725

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Park SY et al. (2005) Reabsorption of neutral amino acids mediated by amino acid transporter LAT2 and TAT1 in the basolateral membrane of proximal tubule. Arch Pharm Res 28: 421–432

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Patel P et al. (2003) Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta. Placenta 24: 39–44

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Sato K et al. (2003) Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 24: 144–148

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Ritchie JWA et al. (2003) A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors. Mol Endocrinol 17: 653–661

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Koopdonk-Kool JM et al. (1996) Type II and type III deiodinase activity in human placenta as a function of gestational age. J Clin Endocrinol Metab 81: 2154–2158

    CAS  PubMed  Google Scholar 

  44. 44

    Zeold A et al. (2006) Metabolic instability of type 2 deiodinase is transferable to stable proteins independently of subcellular localization. J Biol Chem 281: 31538–31543

    Article  PubMed  Google Scholar 

  45. 45

    Friesema EC et al. (2006) Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 20: 2761–2772

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Baqui M et al. (2003) Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. J Biol Chem 278: 1206–1211

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Mortimer RH et al. (1996) Maternal to fetal thyroxine transmission in the human term placenta is limited by inner ring deiodination. J Clin Endocrinol Metab 81: 2247–2249

    CAS  PubMed  Google Scholar 

  48. 48

    Hernandez A et al. (2006) Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 116: 476–484

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Stanley EL et al. (2001) Differential expression of sulfotransferase enzymes involved in thyroid hormone metabolism during human placental development. J Clin Endocrinol Metab 86: 5944–5955

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Kester MH et al. (2002) Characterization of iodothyronine sulfatase activities in human and rat liver and placenta. Endocrinology 143: 814–819

    CAS  Article  PubMed  Google Scholar 

  51. 51

    McKinnon B et al. (2005) Synthesis of thyroid hormone binding proteins transthyretin and albumin by human trophoblast. J Clin Endocrinol Metab 90: 6714–6720

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Moestrup SK et al. (1996) Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis. Proc Natl Acad Sci USA 93: 8612–8617

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Lisi S et al. (2003) Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release. Proc Natl Acad Sci USA 100: 14858–14863

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Kilby MD et al. (1998) Circulating thyroid hormone concentrations and placental thyroid hormone receptor expression in normal human pregnancy and pregnancy complicated by intrauterine growth restriction (IUGR). J Clin Endocrinol Metab 83: 2964–2971

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Banovac K et al. (1986) Triiodothyronine (T3) nuclear binding sites in human placenta and decidua. Placenta 7: 543–549

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Emerson CH et al. (1988) The effect of thyroid dysfunction and fasting on placenta inner ring deiodinase activity in the rat. Endocrinology 122: 809–816

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Yoshida K et al. (1985) Human placental thyroxine inner ring monodeiodinase in complicated pregnancy. Metabolism 34: 535–538

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Santini F et al. (1993) A study of the serum 3,5,3′-triiodothyronine sulfate concentration in normal and hypothyroid fetuses at various gestational stages. J Clin Endocrinol Metab 76: 1583–1587

    CAS  PubMed  Google Scholar 

  59. 59

    Hidal JT and Kaplan MM (1985) Characteristics of thyroxine 5′-deiodination in cultured human placental cells: regulation by iodothyronines. J Clin Invest 76: 947–955

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Thorpe-Beeston JG et al. (1991) Thyroid function in small for gestational age fetuses. Obstet Gynecol 77: 701–706

    CAS  PubMed  Google Scholar 

  61. 61

    Kilby MD et al. (2000) Expression of thyroid receptor isoforms in the human fetal central nervous system and the effects of intrauterine growth restriction. Clin Endocrinol (Oxf) 53: 469–477

    CAS  Article  Google Scholar 

  62. 62

    Jansson T and Powell TL (2006) IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor?—a review. Placenta 27 (Suppl A): S91–S97

    Article  PubMed  Google Scholar 

  63. 63

    Singh PK et al. (2003) Establishment of reference intervals for markers of fetal thyroid status in amniotic fluid. J Clin Endocrinol Metab 88: 4175–4179

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Friesema EC et al. (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22: 1357–1369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the significant contribution made to their work in the human placenta by their long-standing collaborators, Professor J Franklyn and Dr C McCabe. The authors' research is funded by the Health Foundation, the Medical Research Council (UK), Action Medical Research, and the University of Birmingham. Competing interests

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mark D Kilby.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chan, S., Vasilopoulou, E. & Kilby, M. The role of the placenta in thyroid hormone delivery to the fetus. Nat Rev Endocrinol 5, 45–54 (2009). https://doi.org/10.1038/ncpendmet1026

Download citation

Further reading