Endocrine - Thyroid Development
|Embryology - 27 Apr 2017 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Reading
- 4 Development Overview
- 5 Thyroid Timeline
- 6 Thyroid System and Neural Development
- 7 Fetal Thyroid Hormone
- 8 Thyroid Hormone
- 9 Calcitonin
- 10 Maternal Thyroid
- 11 Abnormalities
- 12 Iodine Deficiency
- 13 Maternal Abnormalities
- 14 Environmental Thyroid Disruptors
- 15 Genes
- 16 Thyroid Images
- 17 References
- 18 Additional Images
- 19 Terms
- 20 External Links
- 21 Glossary Links
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.
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.
- Maternal thyroid hormone - required for early stages of brain development (Maternal Thyroid recent studies show both high and low thyroid hormone impact)
- Fetal functions from week 10 - required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)
- Fetal fully functional 16 - 18 weeks - (GA 18-20 weeks)
- Hormones - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)
Maternal thyroid function also changes in early pregnancy, through pituitary changes, resulting in thyroid stimulating hormone (TSH) levels decreasing during the transition from pre-pregnancy to early pregnancy. This change in TSH was less predictable in women with thyroid antibodies. Maternal thyroid hormone crosses the placenta.
Hyperthyroidism in adults is generally treated with antithyroid drugs (ATDs), some of these drugs have been identified as teratogens during pregnancy. (More? Antithyroid Drugs)
Iodine deficiency disorders (IDD) is the single most common cause of preventable mental retardation and brain damage in the world. Iodine (Greek, ioeides = violet) is required for the synthesis of thyroid hormone, a key regulator of neurological development. IDD causes goiters and decreases the production of hormones vital to growth and development. (More? Iodine Deficiency)
Lecture - Head Development | Iodine Deficiency | AbnormalDevelopment - Antithyroid Drugs
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Bartlomiej Budny, Ewelina Szczepanek-Parulska, Tomasz Zemojtel, Witold Szaflarski, Malgorzata Rydzanicz, Joanna Wesoly, Luiza Handschuh, Kosma Wolinski, Katarzyna Piatek, Marek Niedziela, Katarzyna Ziemnicka, Marek Figlerowicz, Maciej Zabel, Marek Ruchala Mutations in proteasome-related genes are associated with thyroid hemiagenesis. Endocrine: 2017; PubMed 28390009
Bo Wang, Ji-Jie Liu, Yan Wang, Lin Fu, Ru Shen, Zhen Yu, Hua Wang, Yuan-Hua Chen, Cheng Zhang, Xiu-Hong Meng, De-Xiang Xu Maternal fenvalerate exposure induces fetal intrauterine growth restriction through disrupting placental thyroid hormone receptor signaling. Toxicol. Sci.: 2017; PubMed 28369636
Rouven Anderson, Ralf Mueller, Sven Reese, Astrid Wehner Evaluation of an automated enzyme-linked fluorescent assay for thyroxine measurement in cat and dog sera. J. Vet. Diagn. Invest.: 2017;1040638717696442 PubMed 28355954
Jing-Hua Pan, Hong Zhou, Xiao-Xu Zhao, Hui Ding, Li Wei, Li Qin, Yun-Long Pan Robotic thyroidectomy versus conventional open thyroidectomy for thyroid cancer: a systematic review and meta-analysis. Surg Endosc: 2017; PubMed 28337546
R G Ahmed Maternal Carbamazepine Alters Fetal Neuroendocrine-cytokines Axis. Toxicology: 2017; PubMed 28267586
- 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
| Endocrinology - An Integrated Approach Stephen Nussey and Saffron Whitehead
St. George's Hospital Medical School, London, UK Oxford: BIOS Scientific Publishers; 2001. ISBN-10: 1-85996-252-1
Copyright © 2001, BIOS Scientific Publishers Limited. Bookshelf
|Chapter 3. The thyroid gland
|Foramen Caecum||Stage 13 and Stage 22 thyroid development|
- thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
- tongue grows, cells descend in neck
- thyroglossal duct - proximal end at the foramen cecum of tongue thyroglossal duct
- thyroid diverticulum - hollow then solid, right and left lobes, central isthmus
- 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
Thyroid System and Neural Development
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
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) molecular structure showing iodine positions (red rings).
|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).|
| A group of enzymes that can modify the thyroid prohormone secreted by the thyroid gland either activating (deiodinase 2) or deactivating (deiodinase 3) thyroid hormone. Their role is thought to regulate the amount of active hormone available locally in a tissue.
Thyroid hormone homeostasis
Calcitonin is synthesized by parafollicular cells (C cells) interspersed in the connective tissue between the follicles and the blood capillary network.
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
Maternal thyroid hormone crosses the placenta possibly by 3 transport protein family mechanisms
- thyoorganic anion-transporting polypeptide
- L-type amino acid transporter
- monocarboxylate transporter
A recent study has identified an association of maternal thyroid function during early pregnancy with child brain morphology and IQ
- Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume
• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume • Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology
In the placenta, the inner ring placental deiodinase inactivates most of the maternal T4 to reverse T3 (rT3). During fetal development to term, up to 30% of the fetal thyroid hormones are of maternal origin.
There are structural anatomical variations and thyroid under and over development, there are a number of abnormalities associated with the persistence of the embryological path of thyroid cell descent, the thyroglossal duct.
In addition there are abnormalities due to low iodine environmental conditions of growth and development. This has subsequent effects upon neural and renal development.
Lingual thyroid gland
The failure of thyroid descent.
|Ectopic thyroid - lingual||Sublingual, suprahyoid and subhyoid||Sublingual and suprahyoid|
The persistence of the thyroglossal duct.
The partial degeneration of the thyroglossal duct.
Abnormal development of the thyroid
Incomplete or excessive descent.
This additional lobe is formed from the isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
Agenesis of Isthmus
|An absence of the isthmus with the lateral lobes positioned independently on either side of the trachea. The normal isthmus measures about 1.25 cm transversely as well as vertically and is located anterior to the second and third tracheal cartilages.|
Occurs approximately 1 in 3000 births, associated with neurological abnormalities. This abnormality can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. The condition can be classified as a permanent and transient form.
American Academy of Pediatrics 2006 - Update of newborn screening and therapy for congenital hypothyroidism "Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis."
Congenital Hypothyroidism Classification
|Primary|| Thyroid dysgenesis (developmental anomaly)
Thyroid dyshormonogenesis (impaired hormone production)
Resistance to TSH binding or signaling
|Central|| Isolated TSH deficiency
Thyrotropin-releasing hormone deficiency
Thyrotropin-releasing hormone resistance
Deficiency in pituitary development transcription factors
|Peripheral|| Resistance to thyroid hormone
Abnormalities of thyroid hormone transport
|Syndromic|| Pendred syndrome
Kocher - Deber - Semilange syndrome
Benign chorea - hypothyroidism
Obesity - colitis
|Transient|| Maternal intake of antithyroid drugs
Transplacental passage of maternal TSH receptor blocking antibodies
Maternal and neonatal iodine deficiency or excess
Heterozygous mutations of THOX2 or DUOXA2
Congenital hepatic hemangioma/hemangioendothelioma
|Based on Table 3 from review on congenital hypothyroidism.|
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.
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.
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: Iodine Deficiency
Thyroid uptake scan images of normal and abnormal thyroids (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.
Thyroid uptake scans image 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."
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.
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)
- 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)
Mouse thyroid Hes1 model
- Ursula Balthazar, Anne Z Steiner Periconceptional changes in thyroid function: a longitudinal study. Reprod. Biol. Endocrinol.: 2012, 10;20 PubMed 22436200
- Sally R James, Jayne A Franklyn, Mark D Kilby Placental transport of thyroid hormone. Best Pract. Res. Clin. Endocrinol. Metab.: 2007, 21(2);253-64 PubMed 17574007
- Mylah Villacorte, Anne-Sophie Delmarcelle, Manon Lernoux, Mahé Bouquet, Pascale Lemoine, Jennifer Bolsée, Lieve Umans, Susana Chuva de Sousa Lopes, Patrick Van Der Smissen, Takako Sasaki, Guido Bommer, Patrick Henriet, Samuel Refetoff, Frédéric P Lemaigre, An Zwijsen, Pierre J Courtoy, Christophe E Pierreux Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembly. Development: 2016; PubMed 27068110
- Yoshitaka Takanashi, Yohei Honkura, Jose Francisco Rodriguez-Vazquez, Gen Murakami, Tetsuaki Kawase, Yukio Katori Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: A study using human fetal sections. Ann. Anat.: 2014; PubMed 25458181
- Gabriella Lania, Zhen Zhang, Tuong Huynh, Cinzia Caprio, Anne M Moon, Francesca Vitelli, Antonio Baldini Early thyroid development requires a Tbx1-Fgf8 pathway. Dev. Biol.: 2009, 328(1);109-17 PubMed 19389367
- Michael B Zimmermann Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am. J. Clin. Nutr.: 2009, 89(2);668S-72S PubMed 19088150
- J B Hazard The C cells (parafollicular cells) of the thyroid gland and medullary thyroid carcinoma. A review. Am. J. Pathol.: 1977, 88(1);213-50 PubMed 18012
- D Glinoer What happens to the normal thyroid during pregnancy? Thyroid: 1999, 9(7);631-5 PubMed 10447005
- Tim I M Korevaar, Ryan Muetzel, Marco Medici, Layal Chaker, Vincent W V Jaddoe, Yolanda B de Rijke, Eric A P Steegers, Theo J Visser, Tonya White, Henning Tiemeier, Robin P Peeters Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol: 2015; PubMed 26497402
- Marie-Louise Hartoft-Nielsen, Malene Boas, Sofie Bliddal, Aase Krogh Rasmussen, Katharina Main, Ulla Feldt-Rasmussen Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy? J Thyroid Res: 2011, 2011;342189 PubMed 21918727 | PMC3170895
- Bipul Kumar Choudhury, Uma Kaimal Saikia, Dipti Sarma, Mihir Saikia, Sarojini Dutta Choudhury, Santanu Barua, Swapna Dewri Dual ectopic thyroid with normally located thyroid: a case report. J Thyroid Res: 2011, 2011;159703 PubMed 21765986 | PMC3134180
- Anuj Jain, Sujata Pathak Rare developmental abnormalities of thyroid gland, especially multiple ectopia: A review and our experience. Indian J Nucl Med: 2010, 25(4);143-6 PubMed 21713222 | PMC3109820 | Indian J Nucl Med.
- Daksha Dixit, M B Shilpa, M P Harsh, M V Ravishankar Agenesis of isthmus of thyroid gland in adult human cadavers: a case series. Cases J: 2009, 2;6640 PubMed 20181171 | Cases J.
- Maynika V Rastogi, Stephen H LaFranchi Congenital hypothyroidism. Orphanet J Rare Dis: 2010, 5;17 PubMed 20537182 | Orphanet J Rare Dis.
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- Petros Perros Thyrotoxicosis and pregnancy. PLoS Med.: 2005, 2(12);e370 PubMed 16363909
- Graciana Diez-Roux, Sandro Banfi, Marc Sultan, Lars Geffers, Santosh Anand, David Rozado, Alon Magen, Elena Canidio, Massimiliano Pagani, Ivana Peluso, Nathalie Lin-Marq, Muriel Koch, Marchesa Bilio, Immacolata Cantiello, Roberta Verde, Cristian De Masi, Salvatore A Bianchi, Juliette Cicchini, Elodie Perroud, Shprese Mehmeti, Emilie Dagand, Sabine Schrinner, Asja Nürnberger, Katja Schmidt, Katja Metz, Christina Zwingmann, Norbert Brieske, Cindy Springer, Ana Martinez Hernandez, Sarah Herzog, Frauke Grabbe, Cornelia Sieverding, Barbara Fischer, Kathrin Schrader, Maren Brockmeyer, Sarah Dettmer, Christin Helbig, Violaine Alunni, Marie-Annick Battaini, Carole Mura, Charlotte N Henrichsen, Raquel Garcia-Lopez, Diego Echevarria, Eduardo Puelles, Elena Garcia-Calero, Stefan Kruse, Markus Uhr, Christine Kauck, Guangjie Feng, Nestor Milyaev, Chuang Kee Ong, Lalit Kumar, MeiSze Lam, Colin A Semple, Attila Gyenesei, Stefan Mundlos, Uwe Radelof, Hans Lehrach, Paolo Sarmientos, Alexandre Reymond, Duncan R Davidson, Pascal Dollé, Stylianos E Antonarakis, Marie-Laure Yaspo, Salvador Martinez, Richard A Baldock, Gregor Eichele, Andrea Ballabio A high-resolution anatomical atlas of the transcriptome in the mouse embryo. PLoS Biol.: 2011, 9(1);e1000582 PubMed 21267068 | PLoS Biol. | Eurexpress transcriptome atlas
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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.
Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), 2003 Oct. Thyroid Gland search Results
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- 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
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- [www.aota.or.kr Asia and Oceana Thyroid Association]
- Society for Endocrinology (UK)
- British Association of Endocrine Surgeons
- [www.aace.com American Association of Clinical Endocrinologists]
- Thyroid Disease Manager USA -- this site includes textbook on the Thyroid. .
- [www.synthroid.com Knoll Pharmaceuticals]- makers of SYNTHROID
- Gray's Anatomy - 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
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