Thyroid gland

Embryology

The pharyngeal apparatus is responsible for the formation of numerous parts of the head and neck region . During the 3rd gestational week, there is hypertrophy of the endoderm in the midline of the primitive pharynx, arising from the first pharyngeal arch between the tuberculum impar and copula; at a point later referred to as the foramen caecum. This thyroid primordium subsequently enlarges and is attached to the floor of the primitive pharynx by a hollow tube known as the thyroglossal duct. The duct communicates with the foramen caecum, which is caudal to the tuberculum impar (median tongue bud) and rostral to the copula (hypobranchial eminence). The thyroid primordium progresses to a thyroid placode located at the base of the tongue ; which subsequently forms the thyroid diverticulum near the apical pole of the aortic sac. 

The thyroid diverticulum then begins its descent towards its final pretracheal destination, passing anterior to the laryngeal cartilages and hyoid bone . During this course, it maintains connection with the floor of the primitive pharynx via the thyroglossal duct. Under normal circumstances, the thyroglossal duct will degenerate and the diverticulum remains suspended in mesenchyme. The solid structure is invaded by vascular mesenchyme, which results in disruption of the solid cellular arrangement. Subsequently, the cells arrange themselves into a web of epithelial cords. The gland regains contact with the aortic sac and subsequently bifurcates. This process is associated with rapid, thyroid stimulating hormone (TSH)-independent, proliferation of the thyroid progenitor cells.

During the 5th week of gestation, the ultimobranchial body (arising from the 4th pharyngeal arch) fuses with the thyroid gland. Prior to this, the ultimobranchial body, which is an endodermal derivative, is invaded by neural crest cells. These cells give rise to the C-cells that participate in calcium homeostasis by producing calcitonin under hypocalcemic circumstances. A structure known as the tubercle of Zuckerkandl is the only remaining structure at the point where the two primitive structures merged. This tubercle can be seen in most adults at the posterior aspect of the gland. It is of clinical significance during thyroidectomies, as the nerve has a close relationship to the recurrent laryngeal nerve.

Around the 7th gestational week, the gland continues to enlarge and the left and right lobes begin to form on either side of the thyroid cartilage in the proximal trachea . They are attached to each other by the thyroid isthmus. In the 10th gestational week, the epithelial cords cluster together into smaller groups. The cells aggregate around a lumen in a single layer and form thyroid follicles. In the 11th week, cellular differentiation occurs that results in the onset of thyroglobulin production and colloid can be seen in the thyroid follicles. By the 20th week, TSH levels begin to rise, resulting in production of thyroid hormones. In the final trimester adult levels of thyroid hormone can be observed in the fetus and the cellular proliferation responds to TSH.

Anatomy

Histology

Unlike other endocrine glands that secrete their products directly into the bloodstream, the thyroid gland stores its products in follicles. The follicles are often clustered together to form numerous lobules that forms the parenchyma of each lobe of the thyroid. The lobules are also separated by septae, which are formed by invading parts of surrounding fibrous capsule. The septae also act as a conduit for neurovascular and lymphatic structures to traverse the gland. Each follicle is formed by either simple low columnar or cuboidal epithelium surrounding a central lumen. When the gland is in a dormant state, the epithelium may also be squamous. 

Thyrocytes (follicular cells) are noted to have a rounded nucleus, and relatively large numbers of organelles (mitochondria, rough endoplasmic reticulum, Golgi bodies, etc.) in-keeping with its function (i.e. protein synthesis and secretion). The rough endoplasmic reticula are more abundant towards the base of the cells, while the Golgi bodies are found towards the apex.

Inadvertently, newly synthesized thyroglobulin, which is temporarily stored in the Golgi apparatus, to be exocytosed into the lumen once the vesicle reaches the cell apex. Apical pole of these cells contains several microvilli. Thyroglobulin is stored as a semi-solid entity known as colloid within the lumen of the follicle. It is one of the key histological features observed on light microscopy, as it stains bright pink with haematoxylin and eosin (H&E). Apically, thyrocytes have numerous zonula occludens (tight junctions), zonula adherens (anchoring junctions), and macula adherentes (spot desmosomes) that holds the cells together.

The basal lamina on which thymocytes reside also function as a scaffold for the parafollicular (C cells) that are also found in the thyroid gland. These endocrine cells are slightly larger, and appear paler (takes up less H&E), than the thyrocytes. They also have numerous organelles to support their function of synthesizing and secreting calcitonin, to assist in maintaining calcium homeostasis.

Although chiefly occupied by thymocytes and parafollicular cells, the stroma of the thyroid gland also contains sparse reticular connective tissue . Additionally, there is also a vast network of fenestrated capillaries that are available to carry thyroid hormones to their main circulation so that they can be distributed systemically. 

Neurovascular supply 

Hormone synthesis

Thyroid hormone synthesis is governed by the hypothalamus . When circulating levels of thyroid hormone is low, the hypothalamus releases thyrotropin releasing hormone (TRH). This hormone then travels to the anterior pituitary glan , where it promotes the release of thyroid stimulating hormone (TSH). TSH enters the bloodstream and travels to the thyroid gland, where it upregulates the transcription and translation of thyroglobulin. The thyroglobulin is packaged by the Golgi body in vesicles, which are exocytosed. The compound is then temporarily stored in the follicular lumen.

Iodine is also important for the production of thyroid hormones. Iodine is provided by dietary means and is concentrated within the cells via basolateral sodium-iodide (Na+-I-) symporters. Iodide within the thyrocytes are then pumped into the follicular lumen via pendrin pumps (apically located iodide-chloride (I--Cl-) pumps). Also, the excess sodium is pumped back into systemic circulation by Na+-K+ ATPase pumps.

At the luminal surface of the follicular cells, iodide is oxidized by peroxidase bound to the microvilli to iodine; which is then used for the organification of the tyrosine moiety of the thyroglobulin protein. The resulting monoiodotyrosine (MIT) can be further organified to diiodotyrosine (DIT). In the presence of thyroperoxidase, MIT and DIT, or two DIT molecules react to form triiodothyronine (T3) or thyroxine (T4), respectively.

The newly synthesized thyroid hormones are still bound to thyroglobulin. This allows the hormones to re-enter the cells by receptor mediated endocytosis. The thyroglobulin part of the molecule will bind to their respective apical receptors and are engulfed by the cells. Alternatively, colloid can be taken up by pinocytosis and re-enter the cell.

Once the vesicle is within the cell, they fuse with other lysosomal vesicles and the protein moiety is degraded by the lysosomal proteases. The remaining T3 and T4 are then released at the basolateral aspect of the cell to be taken up by the fenestrated capillaries. Within the blood, they are bound to albumin, thyroxine-binding globulin (TBG) or thyroxine-binding prealbumin (TBPA) and transported to their target sites. Note that the endocytotic processes may also take up MIT and DIT compounds as well. These can be recycled within the cell and secreted in the follicular lumen for further hormone synthesis.

When the serum levels of thyroid hormones increase, they act at the level of the pituitary gland and hypothalamus to inhibit release of TRH and TSH. Therefore, the hypothalamic-pituitary-thyroid axis operates under a negative feedback mechanism in order to maintain homeostasis. Majority of the hormone released from the gland is in the T4 form. However, at the level of the target cells almost all of the T4 is converted to T3, which is utilized for various metabolic processes. 

Function

At a cellular level, the hormones promote an increase in the total number of mitochondria within the cell, as well as the total surface area of the mitochondria as well. This increase in the quantity of mitochondria also corresponds directly to the increased metabolic rate observed in the organism.

Also at the cellular level, the thyroid hormones cause an increase in the rate of active transport of ions across cellular membranes. This is achieved by increasing the activity of the sodium-potassium adenosine triphosphatase (Na=-K+ ATPase) enzyme, which enhances the transportation rate of the respective ions. This energy dependent activity is also supported by the aforementioned increase in metabolic rate of the organism (i.e. increased ATP production). 

It is interesting to note that the thyroid gland is one of the first endocrine organs to begin functioning in utero. The aforementioned cellular changes along with other tissue specific functions of the thyroid hormone have been shown to promote growth and development. It encourages the absorption and metabolism of carbohydrates, as evidenced by increased absorption of carbohydrates from the gastrointestinal tract, optimization of glycolysis and gluconeogenesis, and increased activity of insulin. Furthermore, there is mobilization of lipids from their fat stores resulting in a decrease in the amount of triglycerides, cholesterol, and phospholipids have also been observed with increased thyroid hormone levels. Majority of the cholesterol is excreted in feces (via bile). These events, as well as other tissue specific activities result in an increase in the basal metabolic rate of the organism.  

In the cardiovascular system, the thyroid hormones have been shown to increase the rate and force of contraction of the heart , and by extension, the overall cardiac output. It has been proposed that this phenomenon is linked to the increased oxygen demand associated with the increased metabolic rate of the organism. The increased blood flow is also necessary to dissipate the excess heat generated from the metabolic reactions that are occurring. The organism’s respiratory function also increases as there is a need to excrete the excess carbon dioxide (as well as to obtain more oxygen) generated by the heightened metabolic processes.

Within the musculoskeletal system, the thyroid hormones promote the reaction of muscle fibres to the neurotransmitters. Consequently, the muscle fibres respond more vigorously with acceptable elevations in thyroid hormones. On the other hand, a decrease in the thyroid hormones would be associated with a reduced muscular response to the neurotransmitters. These hormones also have excitatory effects within the central nervous system ; promoting either anxiety or depression with elevated or depressed hormone levels, respectively.

The effects of the hormone also extends to sexual reproduction; such that patients may experience loss of libido, impotence (in men), or disorders of the menstrual cycle (menorrhagia, polymenorrhea, oligomenorrhea, or amenorrhea). Lastly, other endocrine glands are also affected by the activity of thyroid hormones. Thyroid hormones alter the negative feedback mechanisms of other endocrine glands by increasing the demand for other hormones at the target tissue level. For example, by enhancing the metabolism of glucocorticoid hormones at the liver result in lower circulating levels of the hormones. This is detected by the adrenal glands, which responds by increasing the production of glucocorticoids.