UNSW Embryology

Endocrine Development - Thyroid

© Dr Mark Hill (2008)

Acknowledgements

Introduction

The boundary endoderm in the floor region forms a pocket (marked by the foramen cecum) that separates from the surface and forms the thyroid. Cells originate on the surface of the floor and descend into mesoderm above aortic sac and into the hypopharyngeal eminence as "cords". These cells continue to descend until they reach their final destination in the neck adjacent to the thyroid cartilage.

Foramen cecum	Thyroid cells in hypopharyngeal eminence (Stage 13)	Thyroid gland (Stage 22)

This pathway forms a temporary duct (thyroglossal duct). There are abnormalities of incomplete or excessive descent of these thyroid precursor cells. The thyroid is one of the earliest endocrine organs to differentiate and has an important hormonal role in embryonic development. The early bundle of cells then forms the thyroid by first dividing to form 2 lobes separated by a narrow connecting isthmus. (More? Thyroid References)

Pharyngeal arch 4 pouch forms the superior parathyroid and parafollicular cells of the thyroid.

Page Links: Introduction | Some Recent Findings | Reading | Development Overview | Serial Images | Abnormalities | Thyroid Hormone | Transthyretin | Iodine Deficiency | Maternal Thyroid | Maternal Abnormalities | WWW Links | References | Glossary

Some Recent Findings

Goodman JH, Gilbert ME. Modest Thyroid Hormone Insufficiency during Development Induces a Cellular Malformation in the Corpus Callosum: A Model of Cortical Dysplasia. Endocrinology. 2007 Jun;148(6):2593-7. (Rodent study)

Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May;42(5):379-89.

"Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited.... This review focuses on the genetic aspects of primary congenital hypothyroidism."

John Hopkins Medical Institute Wolfberg, Adam J. and David A. Nagey Abstract # 274: Thyroid Disease During Pregnancy and Subsequent Congenital Anomalies.

The researchers studied 101 women (64 with hypothyroidism and 50 with the overactive version, hyperthyroidism) who gave birth at The Johns Hopkins Hospital between December 1994 and June 1999.

• 108 pregnancies with 114 fetuses
• 21 babies (18%) had birth defects (including cardiac, renal and central nervous systems and other disorders such as sunken chest, extra fingers, cleft lip and palate, and ear deformities)
• 2 fetuses died before being delivered

(More? Thyroid disease 'raises birth risk' Women with thyroid disease are more likely have babies with birth defects even if tests show no problem with the gland during pregnancy, say Johns Hopkins University researchers (BBC report Jan 20, 2002).

Reading

• Human Embryology (2nd ed.) Larson
• The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347
• Before We Are Born (5th ed.) Moore and Persaud
• Essentials of Human Embryology Larson
• Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

Development Overview

24 days - thyroid median endodermal thickening in the floor of pharynx outpouch – thyroid diverticulum.

Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis. growth factors (insulin-like, epidermal) stimulates follicular growth.

Fetal - thyroid hormone initial secreted biologically inactivated by modification, late fetal secretion develops brown fat. Iodine deficiency- during this period, leads to neurological defects (cretinism).

Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels.

Hypothalamic-thyroid (HPT) axis development

Serial Images

Stage 13/14 Embryo: B1- section showing hypopharyngeal eminence | B2- section showing developing thyroid cells in hypopharyngeal eminence | B3- section showing developing thyroid

Stage 22 Human Embryo: C4- portion of Thyroid lateral to trachea (note anterior of section missing) | C5- portion of Thyroid anterior to trachea | C6- connecting stalk between Thyroid and Parathyroid

Stage 22 Human Embryo High Power: HPC3- cross-section of developing Thyroid | HPC2-Location of this Section

Stage 13/14 Images

B1 Superior portion of hypopharyngeal eminence lying in arch of Pharynx.

B2 The primordial Thyroid cords (dark spots) in the Pharynx floor. Note Rathke's pouch in the midline of Pharynx roof.

B2Dark spots within the hypopharyngeal eminence are the "cords" of thyroid precursor cells descending from the pharynx floor to form the thyroid gland in the neck. Thyroid has an important endocrine role in later development.

B3: Rudimentary thyroid ventral to aortic sac (also seen in B2, ventral to the hypopharyngeal eminence).

High Power Images

C2 Human 27mm Embryo

C3 Human 27mm Embryo

Abnormalities

Congenital hypothyroidism - approximately 1 in 3000 births, associated with neurological abnormalities.

Lingual thyroid gland - failure of thyroid descent.

Thyroglossal cyst - persistance of thyroglossal duct.

Thyroglossal fistula - partial degeneration of the thyroglossal duct.

Abnormal development of the thyroid - incomplete or excessive descent.

Pyramidal lobe - from isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.

Childhood hypothyroidism delays ossification and bone mineralization.

(See also NIH Genes & Disease Chapter 41 - Endocrine)

Thyroid Hormone

Thyroid hormone is synthesized in the thyroid gland by the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin.

Thyroxine (T4) - (Mr 777) majority of thyroid hormone derived from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.

Triiodothyronine (T3) - synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4), though T3 is mainly used by tissues. Derived mainly from peripheral monodeiodination of T4 (at the 5' position of the outer ring of the iodothyronine nucleus).

(Data: PubChem)

Links: PubChem - T4 | PubChem - T3 |

Transthyretin

Transthyretin - (TTR, prealbumin) the serum protein which acts as a major carrier of thyroid hormones in the blood.

The protein can also bind plasma retinol-binding protein and may therefore regulate retinoid availability.

Links: OMIM - Transthyretin

Iodine Deficiency

Iodine deficiency disorder (IDD) is the single most common cause of preventable mental retardation and brain damage in the world (More? Abnormal Development - Iodine Deficiency). It is required for synthesis of thyroid hormone, which in turn regulates aspects of neural development.

Worldwide:

• 1.6 billion people are at risk
• IDD affects 50 million children
• 100,000 cretins are born every year

It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women cause miscarriage, stillbirth and mentally retarded children.

A teaspoon of iodine is all a person requires in a lifetime, but because iodine cannot be stored for long periods by the body, tiny amounts are needed regularly. In areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace, food fortification and supplementation have proven highly successful and sustainable interventions.

Iodized salt programs and iodized oil supplements are the most common tools in the fight against IDD.

(Data: ICCIDD)

Prolonged intake of large amounts (excess) of iodide can increase the incidence of goiter and/or hypothyroidism in humans. African Congo appears to be the only country that appears to have a dietary excess.

Links: International Council for the Control of Iodine Deficiency Disorders | Australian Centre for Control of Iodine Deficiency Disorders | Asia-Pacific Iodine Nutrition Map (ICCID)

(More? Abnormal Development - Iodine Deficiency)

Maternal Thyroid

Maternal thyroid related changes during pregnancy:

• stimulation of maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG)
  • occurs mainly near end of first trimester associated with a transient lowering in serum TSH
• increase in serum thyroxine-binding globulin levels
• small decrease in free hormone concentrations (in iodine-sufficient conditions) significantly amplified in iodine restriction or overt iodine deficiency
• trend toward a slight increase in basal thyrotropin (TSH) values between first trimester and term
• modifications of the peripheral metabolism of maternal thyroid hormones

(Text modified from : Glinoer D. What happens to the normal thyroid during pregnancy? Thyroid. 1999 Jul;9(7):631-5.)

Maternal Abnormalities

	(A) Normal (B) Graves disease: diffuse increased uptake in both thyroid lobes. (C) Toxic multinodular goiter (TMNG): “hot” and “cold” areas of uneven uptake. (D) Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid. (E) Thyroiditis: decreased or absent uptake. Image: Perros P. Thyrotoxicosis and pregnancy. PLoS Med. 2005 Dec;2(12):e370.
Thyroid Uptake Scans (Technetium 99)

Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy." (Perros P. Thyrotoxicosis and pregnancy. PLoS Med. 2005 Dec;2(12):e370.)

Graves' disease in mothers can cause thyrotoxic fetus - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

Maternal Hashimoto's Thyroiditis (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

Links: NIH Genes & Disease - Chapter 41 - Endocrine | EPA (USA) - Radiation Technetium

Environmental Thyroid Disruptors

There are several environmental compounds (chemicals) that are suspected of being thyroid disruptors including:

• halogenated phenolic compounds (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl)
• phenol compounds (pentachlorophenol, 2,4,6-triiodophenol)

They have been demonstrated to induce partial agonistic and/or complex competitive/uncompetitive antagonistic responces in cell culture.

Bisphenol A - monomer used to manufacture polycarbonate plastic, possibly disrupts thyroid hormone function and affects neocortical development (accelerating neuronal differentiation/migration). (More? EHP - Bisphenol A Need for a New Risk Assessment)

Genes

Thyroid Transcriptor Factors (TTF) - TTF-1, TTF-2, PAX-8

Fetal hypothyroidism from low levels of these transcription factors- Pit-1, Prop-1, LHX-3

Thyrotropin-releasing hormone (TRH)

Thyroid-stimulating hormone (TSH)

References

Links: Journals | Online Textbooks | Search Textbooks | PubMed | 1999 Refs | Search PubMed | Glossary

Journals

Thyroid Thyroid The official journal of the American Thyroid Association.

Online Textbooks

Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. table of Contents

• The Thyroid Gland
• Surgical anatomy and embryology of the thyroid gland
• Hypothyroidism in infancy and childhood

NIH Genes & Disease Chapter 41 - Endocrine

Developmental Biology (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

• Is the endostyle the precursor of the thyroid gland?
• Environmental thyroid hormone disruptors
• table 13.1. Some derivatives of the neural crest

Molecular Biology of the Cell (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

• table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP

Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), 2003 Oct.

• Thyroid Gland search Results

Search NLM Online Textbooks "thyroid development" : Endocrinology | Molecular Biology of the Cell | The Cell- A molecular Approach

PubMed

Reviews

• Postiglione MP, Parlato R, Rodriguez-Mallon A, Rosica A, Mithbaokar P, Maresca M, Marians RC, Davies TF, Zannini MS, De Felice M, Di Lauro R. Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15462-7.
• Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May;42(5):379-89.
• De Felice M, Postiglione MP, Di Lauro R. Minireview: thyrotropin receptor signaling in development and differentiation of the thyroid gland: insights from mouse models and human diseases. Endocrinology. 2004 Sep;145(9):4062-7. Epub 2004 Jul 1. Review
• Gruters A, Biebermann H, Krude H. Neonatal thyroid disorders. Horm Res. 2003;59 Suppl 1:24-9. Review.

Articles

• Villa-Cuesta E, Modolell J. Mutual repression between msh and Iro-C is an essential component of the boundary between body wall and wing in Drosophila. Development. 2005 Aug 10
• Iskaros J, Pickard M, Evans I, Sinha A, Hardiman P, Ekins R. Thyroid hormone receptor gene expression in first trimester human fetal brain. J Clin Endocrinol Metab. 2000 Jul;85(7):2620-3.

Search PubMed

Search Jun2006 "thyroid development" 9,551 reference articles of which 1,703 were reviews.

Search PubMed: term= thyroid+development

Thyroid Development (1999)

• Follicular cells of the thyroid gland require Pax8 gene function. Mansouri A, Chowdhury K, Gruss P Nat Genet 1998 May;19(1):87-90
  • "The thyroid gland develops from two distinct embryonic lineages: follicular cells (which produce thyroxine) and parafollicular C-cells (which produce calcitonin) are of endodermal and neural crest origin, respectively. Little is known about the molecular mechanisms governing the generation of these different cell types. Mice lacking the transcription factor Ttf1 lack both cell types and thus are unable to develop a thyroid gland. By analysis of Pax8-/- mice, we demonstrate that Pax8 is required for the formation of the follicular cells in the thyroid. We present evidence that Pax8 is necessary for providing cues for the differentiation of competent endoderm primordia into thyroxin-producing follicular cells."
• TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, Taylor BA, Phillips SJ, Simeone A, Di Lauro R EMBO J 1997 Jun 2;16(11):3185-97
  • "Expression of thyroglobulin (Tg) and thyroperoxidase (TPO) genes in thyroid follicular cells occurs in the mouse at embryonic day (E)14.5. Two transcription factors, TTF-1 and Pax-8, have been implicated in transcriptional activation of Tg and TPO, even though the onset of their expression is at E9.5, suggesting that additional events are necessary for transcriptional activation of Tg and TPO genes. We report in this paper the cloning of TTF-2, a DNA binding protein that recognizes sites on both Tg and TPO promoters. TTF-2 is a new forkhead domain-containing protein whose expression is restricted to the endodermal lining of the foregut and to the ectoderm that will give rise to the anterior pituitary. TTF-2 shows transient expression in the developing thyroid and anterior pituitary. In the thyroid, TTF-2 expression is down-regulated just before the onset of Tg and TPO gene expression, suggesting that this transcription factor plays the role in development of a negative controller of thyroid-specific gene expression."
• Regulation of thyroid hormone metabolism during fetal development. Darras VM, Hume R, Visser TJ Mol Cell Endocrinol 1999 May 25;151(1-2):37-47 PubMed
  • "Compared with adults, plasma T3 concentrations in the human fetus are decreased, whereas levels of rT3 and the different iodothyronine sulfates, T4S, T3S, rT3S and 3,3'-T2S, are increased. The low T3 and high rT3 concentrations reflect the preponderance of inner ring versus outer ring deiodinase activity due to high type III iodothyronine deiodinase (D3) expression in fetal tissues, such as liver and brain, the placenta, and perhaps also the uterus, in combination with still incomplete expression of hepatic type I iodothyronine deiodinase (D1) expression. In contrast to humans, D3 is hardly expressed in the fetal rat liver. However, high D3 expression is observed in the embryonic chicken liver which decreases dramatically towards the end of incubation, resulting in a marked increase in plasma T3. Thyroid hormone is essential for the development of the brain, in which local conversion of the prohormone T4 to the active hormone T3 by the type II iodothyronine deiodinase (D2) plays a very important role. In contrast to the rat, however, little is known about the ontogeny of D2 in different human brain areas. The cause of the high concentrations of sulfated iodothyronines in fetal plasma is unknown. In adults, the liver is an important site for the clearance of these conjugates, where they are rapidly degraded by D1. Although fetal human liver expresses significant D1 activity, clearance of iodothyronine sulfates may be defective due to the lack of transporters mediating their hepatic uptake. However, production of iodothyronine sulfates may also be increased in the human fetus, although the responsible sulfotransferases and their location remain to be identified. Sulfation may be a reversible pathway of thyroid hormone inactivation, depending on the recovery of free hormone by sulfatases. However, little is known at present about the characteristics and regulation of these enzymes in fetal human tissues. Further studies are required to increase our understanding of the tissue-specific and stage-dependent regulation of thyroid hormone bioactivity during human development."
• Hormone synthesis and storage in the thyroid of human preterm and term newborns: effect of thyroxine treatment. van den Hove MF, Beckers C, Devlieger H, de Zegher F, De Nayer P Biochimie 1999 May;81(5):563-70
  • "Iodine and thyroglobulin concentrations, as well as iodine, T3, T4 and sialic acid contents of thyroglobulin, were measured in thyroid glands collected postmortem from 42 human premature or term newborns and infants. Three groups were considered: very preterm newborns (24-32 postmenstrual weeks, < 5 days postnatal life), preterm and term newborns (34-41 postmenstrual weeks, < 5 days postnatal life) and infants (born at term, postnatal age 1-8 months). Five very preterm and seven preterm newborns received a daily dose of 10 microg/kg L-T4 for at least 3 days. Thyroid weight and sialic acid content of thyroglobulin progressed with maturation. Intrathyroidal concentrations of iodine and thyroglobulin did not increase significantly before the 42nd week of postmenstrual age. The level of thyroglobulin iodination increased during the postnatal life, except in the very preterm neonates. T4 and T3 content of thyroglobulin was directly proportional to its degree of iodination and positively related to its sialic acid content. L-T4 treatment of preterm newborns increased thyroglobulin iodination and T4-T3 content, without increasing thyroglobulin concentration in the thyroid. It was concluded that the storage of thyroglobulin and iodine in the thyroid develops around term birth. This, associated with the resulting rapid theoretical turnover of the intrathyroidal pool of T4 in Tg, could be an important factor of increased risk of neonatal hypothyroxinemia in the premature infants. The L-T4 treatment of preterm newborns does not accelerate the maturational process of the thyroid gland."

Web Links

• International Council for the Control of Iodine Deficiency Disorders
• World Health Organization- Micronutrient deficiencies Eliminating iodine deficiency disorders
• British Thyroid Association The official site of the British Thyroid Assocation, a non-profit making Learned Society of professional clinical specialist doctors and scientists in the United Kingdom who manage patients with thyroid disease and/or are researching into the thyroid and its diseases in humans.
• WHO Nutrition Guidelines
• American Thyroid Association American Thyroid Association - Patient Information
• Thyroid Foundation of America
• Endocrine Society (USA)
• European Thyroid Association
• Latin-American Thyroid Association
• Asia and Oceana Thyroid Association
• Society for Endocrinology (UK)
• British Association of Endocrine Surgeons
• American Association of Clinical Endocrinologists
• Thyroid Disease Manager USA -- this site includes textbook on the Thyroid.
• Knoll Pharmaceuticals- makers of SYNTHROID
• Gray's Anatomy- 4. The Ductless Glands
  • The thyroid gland and its relations
  • Floor of pharynx of human embryo about twenty-six days old. (From model by Peters)
  • 4b. The Parathyroid Glands

Glossary of Terms

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W |X | Y | Z

Quick Links

UNSW Embryology ISBN: 978 0 7334 2609 4

UNSW CRICOS Provider Code No. 00098G