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ORIGINAL ARTICLE
Year : 2017  |  Volume : 31  |  Issue : 3  |  Page : 195-200

A study on development and morphogenesis of parathyroid gland in the developing human embryo


1 Department of Anatomy, Tripura Medical College, Agartala, Tripura, India
2 Department of Anatomy, IPGME and R, Kolkata, West Bengal, India
3 Department of Anatomy, RIMS, Imphal, Manipur, India

Date of Web Publication17-Aug-2017

Correspondence Address:
Prerana Aggarwal
Department of Anatomy, IPGME and R, Kolkata - 700 020, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_88_14

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  Abstract 


Background: Development of parathyroid gland starts at 5 week of intra-uterine life but it is visible histologically only after 14 weeks.
Objectives: To study the histological changes of the developing parathyroid gland in human fetus at different periods of gestations.
Methods: Parathyroid from 50 fresh human fetuses belonging to both sex and gestational age ranging from 14-40 weeks were studied using Hematoxylin- Eosin, and Masson Trichrome stains.
Results: Early developing parathyroid gland is visible between trachea and oesophagus as small collection of cells invaded by blood vessels and surrounded by loosely arranged connective tissue at 14th week. It is found between trachea and thyroid gland at 16th week with uniformly arranged round cells having vesicular nuclei and pale cytoplasm. A solid nodule with groups and cords of chief cells is visible at 18th week. Blood filled sinusoidal capillaries appear at 24th week. A definite capsule is well visualized at 26th week. A supernumerary parathyroid is also present. Parathyroid can be differentiated from the surrounding adipose tissue, thymus and thyroid follicles at 32nd, 36th and 40th weeks respectively.
Conclusion: Due to diffuse and variable growth, parathyroid gland is not visible on naked eye examination. Histologically it is first observed at 14th week of gestation as small collection of fibroblastic cells which finally form well-defined encapsulated and vascular parathyroid gland. It maybe present near thyroid as its organisation occurs side by side with folliculogenesis of thyroid gland. It maybe present within thymus as both develop from same source. Early division of the primordium may lead to the supernumerary parathyroid.

Keywords: Chief cells, oxyphil cells, thymus, supernumerary gland


How to cite this article:
Mallik S, Aggarwal P, Singh Y I, Singh M M, Singh N S. A study on development and morphogenesis of parathyroid gland in the developing human embryo. J Med Soc 2017;31:195-200

How to cite this URL:
Mallik S, Aggarwal P, Singh Y I, Singh M M, Singh N S. A study on development and morphogenesis of parathyroid gland in the developing human embryo. J Med Soc [serial online] 2017 [cited 2017 Nov 23];31:195-200. Available from: http://www.jmedsoc.org/text.asp?2017/31/3/195/207678




  Introduction Top


The parathyroid glands are small, yellowish-brown, ovoid, or lentiform structures usually lying between the posterior border of the thyroid gland and its capsule, each measuring 6 mm × 3–4 mm × 1–2 mm and weighing about 50 mg.[1] There are usually four glands (in 90% of individuals), two on each side. The superior parathyroid gland is more constant in position; it is usually present within the thyroid's pretracheal fascial capsule, in the middle of the back of the thyroid lobe.[2] The inferior glands are less constant in position.[1] They are usually present near the inferior end of the posterior border of the thyroid gland, within or outside its fascial sheath.[3],[4],[5] The glands are not necessarily on the same level on each side. They may be outside the fascial sheath in a variable position in the neck or in the superior or posterior mediastinum.[2] Parathyroid glands vary in number; from minute islands of parathyroid tissue scattered in connective tissue at their usual position to six glands.[6],[7] These variations are surgically important.[8] Both superior and inferior parathyroid glands are usually supplied by inferior thyroid arteries. The veins from gland drain into thyroid veins and its lymphatics drain mainly into deep cervical nodes.[1]

Superior parathyroid glands develop from the dorsal region of the endodermal pouch of fourth pharyngeal arch whereas inferior ones develop from that of the third arch.[9]

Histologically, the microscopic cells of parathyroid are arranged in irregular spiral columns, but in sections, they appear only as small clumps of cells. Connective tissue of the capsule and septa contains fat cells, which increase in number with age.[10] Epithelial cells are of two types - chief or principal cells and oxyphil cells. Chief cells are the most numerous.[11] They are sometimes divided into clear and dark forms. Clear chief cells are few in number, have large vesicular nuclei and a clear, pale-staining cytoplasm that contains few granules. Dark chief cells have smaller nuclei and fine granules bounded by membrane. Both forms are rich in glycogen. The appearance of human chief cells differs according to the level of their activity.[12] They produce parathormone which regulates blood ion levels of calcium and phosphate.[13] Its secretion and release depends on calcium levels in the blood and not on the pituitary hormone.[11] Oxyphil cells are larger in size, few in number, and more acidophilic than the chief cells. They are seen more commonly in older individuals.[10] Their function is not known, but they may represent old chief cells that no longer secrete parathormone.[11]

The specific aims and objectives of the present study are to observe the development of the parathyroid glands in the human fetuses at different intrauterine age period, to identify the structural and functional units of parathyroid tissue, i.e., the principal or chief cells, and to see various locations of parathyroid glands histologically.


  Materials and Methods Top


The study was conducted over a period of 1 year on fifty freshly available human fetal specimen without any gross anatomical abnormality, belonging to both sexes and of different gestational ages ranging from 14 to 40 weeks, in the Department of Anatomy of a reputed college in Imphal after obtaining informed consent from the parents and ethical clearance from the concerned authorities. The ages of the fetuses were assessed from the obstetrical history, crown-rump length (CRL), and gross features before fixation. The fetal specimens were categorized into four groups based on their gestational age as: Group I (14–20 weeks), Group II (21–27 weeks), Group III (28–34 weeks), and Group IV (35–40 weeks). These specimens were fixed in freshly prepared solution of 10% formal saline for 2 weeks. After proper fixation of the fetuses, parathyroid glands along with the thyroid gland, a piece of thymus and the anterior surface of the trachea were dissected. The tissue was secondarily fixed in neutral buffered formalin for 10–15 days. Some tissues were also fixed secondarily in Bouin's fluid for 1 day. After proper fixation, the tissues were subjected to standard procedures of gradual dehydration, clearing, wax impregnation, embedding, and paraffin block making. Ribbons of 5–10 μ thickness were obtained and mounted on clean glass albuminous slides, which were dried and stored in incubator overnight at 37°C. The slides were stained with Hematoxylin and Eosin (H and E). Special staining was done using Masson's Trichrome Stain for differentiation between the collagen fibers and muscle fibers. Detailed microscopic analysis of the prepared slides was carried out under ×10 and ×40 objectives of light microscope to observe general morphology and cellular architecture. Slides showing maximum clarity were chosen and photographed. Particulars of the sex, gestational age, CRL, weight of fetus, and histology were duly noted down. The findings and data were compiled and compared with the works of the previous workers.


  Results and Observation Top


Appearance of parathyroid gland regarding its location and relevant histological pictures obtained from fetuses are discussed groupwise below.

Group I: 14–20 weeks

  • At 14 weeks: Low power (×10), light microscopy (H and E) observation shows a small collection of cells surrounded by loosely arranged connective tissue and invaded by blood vessels. This collection of cells which is present by the side of trachea is inferred as the early developing parathyroid gland [Figure 1]a. Under higher magnification (×40), the cells are seen to have centrally placed vesicular nucleus and lightly eosinophilic cytoplasm. These fibroblastic cells are interpreted as the future chief cells and are accompanied by embryonic mesenchymal cells with fine connective tissue [Figure 1]b. The cells are arranged in groups and cords, thereby leaving spaces which represent future blood capillaries
  • At 16 weeks: Low power light microscopy (H and E, ×10) observation shows the cells are arranged densely. The anlage of parathyroid gland is seen surrounded by loose embryonic connective tissue at the angle between the trachea and thyroid gland [Figure 2]a. Under higher magnification (×40), the cords of cells show more uniform pattern with branching. The nuclei of the developing chief cells seem to be vesicular and round with pale cytoplasm. Fine threads of embryonic connective tissue fibers support them. Thin-walled blood vessels in between the cell cords are better now evident [Figure 2]b
  • At 18 weeks: Under low power (×10), the developing parathyroid gland is visible in the form of a solid nodule surrounded by a thin capsule [Figure 3]a. High power (×40) microscopy (H and E stain) gives even better account of organization of groups and cords of cells. There is increase in size and uniformity in cell cord formation. Intercellular capillaries are also better organized [Figure 3]b.
Figure 1: Cytoarchitecture of parathyroid gland at 14 weeks (a) developing parathyroid gland (H and E stain, ×10), (b) fibroblastic cells (H and E stain, ×40)

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Figure 2: Cytoarchitecture of parathyroid gland at 16 weeks (a) parathyroid gland anlage between trachea and developing thyroid follicles (H and E stain, ×10), (b) cluster of chief cells (H and E stain, ×40)

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Figure 3: Cytoarchitecture of parathyroid gland at 18 weeks (a) a nodule of parathyroid gland surrounded by a thin capsule (H and E stain, ×10), (b) capillaries in between the cell cords (H and E stain, ×40)

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Group II: 21–27 weeks

  • At 24 weeks: Under low power (×10), light microscopy (H and E stain) cells are seen in more compactly arranged manner. The developing chief cells are surrounded by a capsule, and large thin-walled blood vessels invade the cellular cluster. The cells are surrounded by loose areolar tissue which is seen separating the developing parathyroid gland from trachea and esophagus [Figure 4]a. High-power microscopy reveals more uniformly arranged chief cells in groups and cords compared to earlier weeks. Nuclei are same, i.e., spherical and vesicular and cytoplasms are pale. Blood filled, thin-walled sinusoidal capillaries are now well visualized in between the cell cords [Figure 4]b
  • At 26 weeks: The Masson's Trichrome-Stained developing parathyroid gland is seen in two pieces with intervening large thin-walled blood vessel in the angle between the trachea and thyroid gland under low power. A well-defined capsule surrounds the parathyroid gland. The extra gland maybe a supernumerary gland [Figure 5]a. Under high power (×40), collagen fibers forming a component of gland's architecture are well visualized. Group of cells along with the sinusoidal capillaries show increased vascularity [Figure 5]b.
Figure 4: Cytoarchitecture of parathyroid gland at 24 weeks (a) the loose areolar tissue is separating the parathyroid gland from trachea and esophagus (H and E stain, ×10), (b) increased vascular component of the gland and the developing chief cells that are uniformly arranged in groups and cords (H and E stain, ×40)

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Figure 5: Cytoarchitecture of parathyroid gland at 26 weeks (a) two pieces of parathyroid gland with intervening blood vessel (Masson's trichrome stain, ×10), (b) collagen fibers forming the glandular architecture (Masson's trichrome stain, ×40)

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Group II: 28–34 weeks

  • At 32 weeks: Under low magnification (H and E stain), developing parathyroid gland seems well organized, supported, and surrounded by a well-formed capsule and invaded by blood vessels. The capsule is seen separating parathyroid gland from the surrounding adipose tissues [Figure 6]a. High magnification (×40) shows that the well-organized chief cells have rounded vesicular nuclei with pale-staining cytoplasm. Collagenous fibers in capsule and within the gland are clearly visible. Thin-walled capillaries are also present [Figure 6]b.
Figure 6: Cytoarchitecture of parathyroid gland at 32 weeks (a) the capsule separates parathyroid gland from the surrounding adipose tissues (H and E stain, ×10), (b) cell cords and sinusoids (H and E stain, ×40)

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Group IV: 35–40 weeks

  • 36 weeks: The developing chief cells of parathyroid gland are separated from the thymic cells by thin zone of collagenous fibers. The thymic cells are darker stained and their lymphocytes are densely arranged; whereas, parathyroid chief cells are light stained with round nuclei [Figure 7]a and [Figure 7]b. This can be inferior parathyroid gland
  • 40 weeks: Under low power (×10), thyroid follicles are well-visualized just above the nodular parathyroid gland. The parathyroid chief cells show round nuclei and pale-stained cytoplasm. The presence of capillaries in between the cords of chief cells is evident. Both the glands seem to be surrounded by separate capsules. This parathyroid gland may be inferred as superior parathyroid gland [Figure 8].
Figure 7: Cytoarchitecture of parathyroid gland at 36 weeks (a) a zone of collagen separating thymus from the parathyroid gland (H and E stain, ×10), (b) dark-stained thymic cells are more densely arranged than the lightly stained parathyroid cells (H and E stain, ×40)

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Figure 8: Cytoarchitecture of parathyroid gland at 40 weeks follicular thyroid and parathyroid glands enclosed in separate capsules (H and E stain, ×10)

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  Discussion Top


In the present study, the developing parathyroid gland could not be identified by the naked eye examination after dissection and fixation due to its variable and diffuse growth but was visible histologically, first seen at 14 weeks of gestation.

The early developing parathyroid gland which is identified histologically at 14 weeks is present by the side of trachea in the form of a small collection of cells surrounded by loosely arranged connective tissue [Figure 1]a and [Figure 1]b. At 16 weeks' gestation, it is found in the angle between the trachea and the thyroid gland as a dense mass consisting of primitive cords of cells, which are branching and anastomosing. Thin-walled blood vessels are seen intervening the mass [Figure 2]a and [Figure 2]b. At 18 weeks, a solid nodule with a thin capsule consisting of the uniform cords of cells with intervening capillaries is evident [Figure 3]a and [Figure 3]b. According to Hamilton and Boyd, the parathyroid glands are developed from separate pouches, i.e., III and IV and show similar histogenesis. Parathyroid tissue first becomes recognizable in the endodermal walls of the pharyngeal pouches concerned in embryos of about 8 mm CRL. The differentiating parathyroid cells in each pouch multiply rapidly to from a small solid nodule, and at the same time, they increase in size and develop staining characteristics that distinguish them clearly from the endodermal cells of the remainder of the pharyngeal pouch. In particular, the cytoplasm is less acidophilic, and this feature combined with the large size of the cells (about 12 μ or more in diameter) gives the developing parathyroid gland a less dense appearance than the other epithelial cells in its neighborhood. This variety of parathyroid cell which is characteristic of these early stages has been called the “primordial” cell. At the time of separation of the parathyroid buds from the related pharyngeal pouches, the “primordial” cells are the only ones to be found in the parathyroid glands.[14] According to Gray's Anatomy, the parathyroid gland develops from interaction between III and IV pharyngeal pouch endoderm and the local cardiac (vagal) neural crest mesenchyme. The cardiac neural crest mesenchyme provides the connective tissue elements, and invading angiogenic mesenchyme gives rise to fenestrated capillaries and lymphatics.[15] The interaction could be in the primordium of thyroid and the migrated parathyroid primordium with the cardiac neural crest mesenchyme and vascularization.[1]

At 24 weeks, the parathyroid gland is seen in vicinity of trachea and the esophagus. Vascularization of the gland is increased gradually henceforth [Figure 4]a and [Figure 4]b. A well-formed capsule surrounding the gland is visible only at 26 weeks after the Masson's Trichrome Staining. This capsule separates the nodular parathyroid gland from the thyroid glandular tissue. The developing parathyroid gland is present in two pieces as encapsulated mass within the angle between the trachea and thyroid gland. It could be a case of supernumerary parathyroid gland [Figure 5]a. The growth of the parathyroid gland may be outside the thyroid gland or within its capsule. This variable growth and supernumerary parathyroid gland is also stated by Moore and Persuad, which states that the supernumery glands probably result from division of the primordium of original glands.[16] According to Akerstrom et al., most often, the supernumerary gland was a fifth parathyroid gland usually near thymus.[17] Hamilton and Mossman also states that during their separation from the related pharyngeal endodermal pouches; the parathyroid frequently shows slight segmentation or small separated partitions. It is from this undoubtedly that the parathyroid and accessory parathyroid gland arise.[14]

At 32 weeks, the parathyroid gland is seen embedded within the adipose tissue [Figure 6]a and [Figure 6]b. In the specimen of 36 weeks, it is seen within the thymic tissue [Figure 7]a and [Figure 7]b. It can be inferior parathyroid gland and can be explained embryologically. The epithelium of the dorsal region of third pouch proliferates into inferior parathyroid glands and ventral into thymus. The primordia of thymus and parathyroid glands loose their connection with pharynx and thymus moves downward pulling with it inferior parathyroid gland.[10] Later, inferior parathyroid gland gets separated from the thymus and lies on the dorsal surface of the thyroid gland.[14] Sometimes, ventral thymic rudiment persists and is connected with dorsal parathyroids III.[18] Akerstrom et al. have observed that the inferior parathyroids most often lay somewhat more ventrally, close the lower thyroid pole or in the upper thymus or thyrothymic ligament. He also states that an inferior parathyroid gland fails to descend and remains near the bifurcation of the common carotid artery. In other cases, it may accompany the thymus into the thorax.[17]

At 40 weeks, the thyroid follicles are well visualized just above the nodular parathyroid gland [Figure 8]. This parathyroid gland may be inferred as superior parathyroid gland because of its association with the thyroid follicles. The superior parathyroid glands are more constant in position and usually lie within the thyroid's pretracheal fascial capsule, in the middle of the back of the thyroid lobe.[2]

The chief cells first appear at 14 weeks with centrally placed vesicular nucleus and lightly eosinophilic cytoplasm as visible under higher magnification. The number of chief cells increases gradually; they are arranged in well-organized groups and cords. The nuclei become more vesicular and round. The number of mesenchymal cells is also increased gradually and are seen scattered in between the chief cells. Vascularity of the whole mass is increased more after 26 weeks; blood-filled sinusoids present in between the cells are replaced by thin-walled capillaries. The capsule is well defined at 26 weeks better stained by Masson-trichrome. In later weeks, connective tissue within the gland is also visible [Figure 6]b, [Figure 7]b and [Figure 8]. As mentioned in few books, a network of reticular fibers supports the parenchyma, which is composed of masses and cords of epithelial cells. There are two types of cells present in parathyroid gland: the chief (principal) cells and oxyphil cells. The chief cells are most numerous, are round, and have a pale, slightly acidophilic cytoplasm whereas less numerous oxyphil cells are larger and more acidophilic than them. However, oxyphil cells are present in older individuals.[10],[11] Di Fiore's Atlas of Histology also states that the parathyroid gland cells arrange into anastomosing cords and clumps, instead of the follicles filled with the secretory material colloid surrounded by follicular cells of the thyroid gland.[11] In present study also, there are no colloid-filled follicles in parathyroid gland like thyroid gland neither are the chief cells as dark as lymphocytes of thymus [Figure 2]a, [Figure 7]b and [Figure 8].


  Conclusion Top


Even though the parathyroid gland starts developing at 5 weeks of intrauterine life (IUL), it is first identified histologically at 14 weeks of IUL. It could not be identified on naked eye examination.

As per findings of the present work, early developing parathyroid gland identified at 14 weeks is present by the side of the trachea. The growth of the parathyroid gland may be within the capsule of the thyroid gland or outside it. A solitary parathyroid gland with a thin capsule is present at 18 weeks. When occurring within the capsule of the thyroid gland, no definite capsule around the parathyroid gland could be seen upto 26 weeks. Organization of the parathyroid gland as nodular structure occurs side by side with folliculogenesis of the thyroid gland. Vascularization of the mesenchymal stromal tissue and the primordial cells are well visualized as early as 14 weeks. It develops gradually from sinusoids to thin-walled capillaries. Vascularization increases from 24th week to full term. The presence of parathyroid gland with the thymic tissue can be due to the same source of origin of inferior parathyroid gland and thymus and their nonseparation. Supernumerary glands may result from division of the primordium of original gland.

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  References Top

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Moore KL, Persaud TV. The Developing Human: Clinically Oriented Embryology. 8th ed. Philadelphia: Saunders Elsevier; 2008. p. 167-9.  Back to cited text no. 16
    
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Akerstrom G, Malmaeus J, Bergstrom RJ. Surgical anatomy of human parathyroid glands. Praque Med Rep 2006;107:261-72.  Back to cited text no. 17
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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