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Thyroid & parathyroid

Thyroid - general

Embryology

Author: Andrey Bychkov, M.D., Ph.D.

Last author update: 1 May 2017

Last staff update: 28 August 2023

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PubMed search: Embryology [title] thyroid

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Table of Contents

Cite this page: Bychkov, A. Embryology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidembryology.html. Accessed April 18th, 2024.

Definition / general

Thyroid originates from a medial anlage and two lateral anlagen, which fuse during development
- Medial anlage gives rise to the major portion of each lateral lobe, isthmus and thyroglossal duct with pyramidal lobe; it is a source of follicular cells
- Lateral anlagen (ultimobranchial bodies) give rise to C cells, solid cell nests and portions of the lateral thyroids
- Recent articles suggest that both medial and lateral anlagen are of endodermal origin and the earlier theory of a neural crest origin of thyroid C cells is dubious (Development 2015;142:3519, Eur Thyroid J 2016;5:79)
Thyroid development starts from the late 3rd to early 4th weeks of gestation, then the fetal thyroid gland develops rapidly until the 4th month of intrauterine growth
Thyroid development is complete with the onset of thyroid hormone synthesis
Thyroid is the first endocrine organ to develop in embryo, which points to its importance

Diagrams / tables

Summary table:

Event	Week	Day
Specification of the thyroid domain in the ventral endoderm	week 3	E20 - 22
Thyroid bud (medial anlage) formation	weeks 3 - 4	E20 - 24
Thyroid bud begins migration	week 4	E24 - 28
Formation of the lateral anlagen (ultimobranchial bodies)	weeks 4 - 7
Migration of lateral anlagen	weeks 5 - 7
Thyroglossal duct disappears	weeks 5 - 6	E30 - 40
Thyroid migration is complete	weeks 7 - 8	E45 - 50
Fusion with ultimobranchial bodies	weeks 7 - 9	E44 - 60
Onset of folliculogenesis	week 10	E70
Release of thyroid hormone	weeks 10 - 12	E80

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Embryonic development of thyroid gland

Branchial arches

Thyroglossal duct

Relation to vessels

Interplay of transcription factors

Organogenesis

Medial thyroid anlage originates from endoderm in the ﬂoor of primordial pharynx (ventral endoderm of the foregut) (Carlson: Human Embryology and Developmental Biology, Fifth Edition, 2013)
- Local mesodermal inductive signals render specification of a small number of endodermal cells (as few as 60 in mouse) to be destined to a thyroid fate
- Endodermal thickening (placode) begins to extend into the surrounding mesodermal mesenchyme forming thyroid bud
- Thyroid primordium soon elongates to form a prominent downgrowth (outpouching) called the thyroid diverticulum
- This area lies caudad to the first pharyngeal pouches (between the first and second branchial arches) and the developing tuberculum impar of tongue, which corresponds to the apex of the foramen cecum on the developing tongue
- Thyroid bud formation takes place during days 20 - 24 post conception
Thyroid diverticulum migrates deep into the neck
- Descent of thyroid bud is due to elongated cephalad embryonic growth rather than active descent (Stocker and Dehner: Stocker and Dehner's Pediatric Pathology, Third Edition, 2010)
- Initial descent of thyroid primordium follows the primitive heart and occurs anterior to the pharyngeal gut
- The route of migration passes ventral (or anterior) to the developing hyoid bone and laryngeal cartilages
- The pathway of caudal extension of thyroid diverticulum is determined by the pattern of arteries in the neck and further modified during pharyngeal development (Carlson: Human Embryology and Developmental Biology, Fifth Edition, 2013)
- Descent is during weeks 5 to 7 of gestation
During the migration, medial thyroid anlage remains attached to the base of tongue by a narrow tube, the thyroglossal duct
- Position of thyroglossal duct is modified by development of the hyoid bone (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- Thyroglossal duct loses its lumen and degenerates by weeks 8 - 10, when thyroid reaches its normal position
- Proximal opening of thyroglossal duct persists as a small pit in the dorsum (posterosuperior surface) of the tongue known as foramen cecum
- Distal portion of thyroglossal duct may persist as the pyramidal lobe of thyroid, which is found in almost half the population
Shaping and landing
- Shortly after starting descent, thyroid diverticulum appears as a hollow vesicular structure
- During further migration, it solidifies and the tip of thyroid diverticulum bifurcates into right and left lobes (evident early in week 5) connected by the isthmus (visible during week 6)
- By the end of week 7 of gestation thyroid gets its definitive shape and final position in the neck anterior to the trachea between 2nd and 5th tracheal ring
Paired lateral thyroid anlagen arise from anterior endoderm that form transient embryonic structures called the ultimobranchial bodies (UBB)
- Ultimopharyngeal or ultimobranchial body is a small gland found in vertebrates, which participates in calcium homeostasis in addition to parathyroid
- The early human UBB develops from the pharyngeal endoderm
  - It was long believed that UBB was invaded by neural crest cells, which further differentiate into C cells
  - Neural crest is a transient tissue initially found at the junction of the neural groove and ectoderm and forming an intermediate zone between the surface ectoderm and neural tube after fusion of neural groove into the tube
  - The most recent concept suggests that UBBs are of endodermal but not of neural crest origin (Development 2015;142:3519, Eur Thyroid J 2016;5:79)
- Geographically UBBs originate from the ventral elongated part of the IV - Vth branchial pouch complex and develop during weeks 5 to 7 of fetal life (Mills: Histology for Pathologists, Fourth Edition, 2012)
  - In vertebrates, UBB typically arises from the Vth pharyngeal pouch, which corresponds to the ventral portion of the IVth pharyngeal pouch in humans; whether Vth pharyngeal pouches actually exist in humans is debatable, hence a term "IV - Vth branchial pouch complex" is used instead
- While still connected to the pharynx, paired UBBs start migration downward and at weeks 7 to 8, they separate from the pharynx and the parathyroid
- At weeks 8 to 9, lumens of UBBs become obliterated by proliferating cells and they appear as solid masses
- Fusion of the medial and both lateral anlagen occurs in the upper dorsolateral aspect of thyroid, which produces thickenings of the gland known as the tubercles of Zuckerkandl (Terris: Thyroid and Parathyroid Diseases: Medical and Surgical Management, Second Edition, 2016)
- UBB cells disseminate within the thyroid, mainly giving rise to C cells but also contributing to follicular cells (thyroid weight increases 30% after fusion)
- Site of fusion of the median and lateral anlagen (upper dorsolateral thyroid) determines restriction of C cells and solid cell nests to area within the middle to upper third of the lateral lobes, while the upper and lower poles and the isthmus are largely devoid of C cells
Differentiation and functional maturation continues during weeks 8 to 12 (see Histogenesis below)
Weight dynamics
- Weight of thyroid gland increases in a nearly linear manner from about 5 to 20 mg to 250 to 500 mg between weeks 10 and 20 (Histol Histopathol 1997;12:79)
- During the second trimester, the gland weight increases 7 to 8 fold, from approximately 100 to 125 mg to 700 to 800 mg
- Tables with a weight of fetal thyroid in relation to gestational age and body weight are available (Anat Rec 1964;148:123, Anat Rec 1971;171:227, Pediatr Dev Pathol 2002;5:559)

Histogenesis

Primordium
- Thyroid primordium consists of a solid mass of proliferating endodermal cells
- This cellular aggregation breaks up into a network of epithelial cords and clusters as it is invaded by the surrounding vascular mesenchyme (by week 9)
Maturation (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- Precolloid stage with a pattern of cords and tubular structures and well defined mesodermal septa but there is no colloid (at about 10 weeks)
- Primitive follicles with forming lumen are first seen by weeks 10 - 11
- Colloid stage with colloid collection (by week 12) and well developed follicles (by week 14)
  - Follicular cells appear morphologically well developed at ultrastructural level after week 13, earlier changes are also well documented by electron microscopic study (Cell Tissue Res 1983;233:693)
- Colloid secretion proceeds and by week 16 noniodinated thyroglobulin is present in many of the widely dispersed follicular spaces
- The gland rapidly grows between weeks 16 and 18 with appearance of increasing number of colloid filled follicles and establishment of a rich capillary network
UBB derived structures (Mills: Histology for Pathologists, Fourth Edition, 2012)
- After fusion with medial thyroid at week 9, UBB enters into a dissolution phase and divides into a central, thick walled, stratified epithelial cyst and peripheral component
- Peripheral component scatters among the follicles to provide parafollicular cells (C cells)
  - Histologically C cells have more ovoid nuclei and pale cytoplasm, they locate subfollicular or interstitially with close relation to capillaries
  - C cells may be identified tentatively by light microscopy around week 12 but the characteristic neurosecretory granules are found around week 16 at the earliest (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
  - The cells can be identified confidently as C cells by about 20 weeks, using immunohistochemical techniques
  - The neonatal gland contains 10x more C cells than the adult thyroid, as the number of C cells diminishes with age (Stocker and Dehner: Stocker and Dehner's Pediatric Pathology, Third Edition, 2010)
- In postnatal life, the central epithelial cyst derived from UBB largely disappears, its occasional remnants are found in thyroid interstitium in the form of solid cell nests
Histology of perinatal thyroid (Khong: Keeling's Fetal and Neonatal Pathology, Fifth Edition, 2015)
- Small uniform follicles lined by cuboidal to low columnar epithelium with round nuclei and containing a variable amount of colloid
- Follicular size and colloid content vary from lobe to lobe and even within each lobule and may reflect fluctuations in the activity of each follicle
- C cells appear as relatively polygonal, paler stained cells usually lying within the walls of follicles between basement membrane and follicular epithelium
- Stroma is more abundant than in adult thyroid
- Perinatal thyroid gland may have areas with more solid appearance due to colloid depletion and collapse of the glandular parenchyma probably resulted from stress of labor and delivery

Functional development

Thyroid gland begins to function at weeks 10 - 12
- By week 10 of gestation, follicles containing some colloid material are evident and a few weeks later, the gland begins to synthesize noniodinated thyroglobulin
- Actual synthesis of thyroglobulin detected with sensitive techniques begins when thyroid is still a solid mass at the base of tongue, which is long before follicle formation and morphologically identifiable colloid secretion (J Clin Endocrinol Metab 1969;29:849)
Hypothalamic - pituitary - thyroid axis
- Early growth and development is independent of TSH (Best Pract Res Clin Endocrinol Metab 2008;22:57)
- Hypothalamic thyrotropin releasing hormone (TRH) is present by about weeks 8 - 10 of gestation
- Pituitary begins releasing TSH at about the same time
- Full regulatory interactions within hypothalamic - pituitary - thyroid axis are established between weeks 12 and 18, after that thyroid gland may be considered to be under autonomous fetal control
- Under normal circumstances, maternal thyroid stimulating factors do not have an effect on fetal thyroid function
Blood levels of hormones
- T3 is present by late in the 4th month and T4 by the end of the 5th month; overall significant fetal hormone secretion is present after week 20 (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- TSH levels grow sharply around weeks 16 - 18, the rise is slowing to plateau at about week 28 and finally reaching adult levels by week 35
- Iodine uptake and T3 / T4 levels reflect the above TSH fluctuations
- Until midgestation fetus depends on maternal supply of thyroid hormone, which is reduced to 30% later in the pregnancy; T3 / T4 synthesis also depends on maternal iodine supply via placenta (Khong: Keeling's Fetal and Neonatal Pathology, Fifth Edition, 2015)

Regulation

Specification of thyroid primordium begins under inﬂuence of FGF signaling pathways
Morphogenetic process during early embryologic stages (bud formation) is regulated by coordinated action of four major transcription factors: NKX2-1 (TTF1), FOXE1 (TTF2), PAX8 and HHEX
- Mutations in these genes cause thyroid dysgenesis, often as a part of syndrome with multiple organ involvement
Contributing effect of mesoderm derived mechanisms, e.g. mediated by TBX1 and FGF family
TSHR gene along with Thyroglobulin (Tg), Thyroid peroxidase (TPO), NIS, HOXA3, FGFR2 and NKX2 family genes are expressed during late stages of fetal development (after migration of medial anlage is completed)
Murine models suggest that transcription factors NKX2-1 and MASH1 influence development of C cells (Dev Dyn 2006;235:1300, Dev Dyn 2007;236:262)

IHC phenotype

Medial anlage: TTF1+, TTF2+ (FOXE1), PAX8+
Lateral anlagen: TTF1+, PAX8+
Fetal thyroid: Tg+, calcitonin / mCEA and the above
More markers (Mills: Histology for Pathologists, Fourth Edition, 2012):
- Transient expression of ghrelin
- Gal1 but not Gal3 in fetal stroma
- Ki67 proliferation index is highest (~15%) between weeks 10 and 20, then diminishes through the latter half of gestation, dropping to < 0.5% at birth (J Clin Endocrinol Metab 2006;91:2672)

Developmental abnormalities

Manifested as congenital hypothyroidism
- Failure of thyroid development (dysgenesis), including aplasia and hypoplasia
- Dyshormonogenetic goiter due to inherited defects in thyroid hormone synthesis
Manifested as neck mass
- Persistence of thyroglossal duct with cyst formation
- Branchial cleft cysts
Other remnants and ectopias
- Lingual thyroid
- Cervical and extracervical ectopic thyroid tissue due to failure of normal migration
- Presence of pyramidal lobe is considered as mild thyroid developmental anomaly
Other syndromes
- 22q11.2 deletion syndrome (DiGeorge syndrome)