hormones act by crossing the cell membrane and binding to intracellular nuclear thyroid hormone receptors tr-α1, tr-α2, tr-β1, and tr-β2, which bind with hormone response elements and transcription factors to modulate dna transcription. in addition to these actions on dna, the thyroid hormones also act within the cell membrane or within cytoplasm via reactions with enzymes, including calcium atpase, adenylyl cyclase, and glucose transporters. hormone production synthesis of the thyroid hormones, as seen on an individual thyroid follicular cell: - thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory pathway to enter the colloid in the lumen of the thyroid follicle by exocytosis. - meanwhile, a sodium-iodide (na/i) symporter pumps iodide (i−) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms. - this iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner. - in the colloid, iodide (i−) is oxidized to iodine (i0) by an enzyme called thyroid peroxidase. - iodine (i0) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues). - in conjugation, adjacent tyrosyl residues are paired together. - the entire complex re-enters the follicular cell by endocytosis. - proteolysis by various proteases liberates thyroxine and triiodothyronine molecules, which enters the blood by largely unknown mechanisms. the thyroid hormones are created from thyroglobulin. this is a protein within the colloid in the follicular lumen that is originally created within the rough endoplasmic reticulum of follicular cells and then transported into the follicular lumen. thyroglobulin contains 123 units of tyrosine, which reacts with iodine within the follicular lumen. iodine is essential for the production of the thyroid hormones. iodine (i0) travels in the blood as iodide (i−), which is taken up into the follicular cells by a sodium-iodide symporter. this is an ion channel on the cell membrane which in the same action transports two sodium ions and an iodide ion into the cell. iodide then travels from within the cell into the lumen, through the action of pendrin, an iodide-chloride antiporter. in the follicular lumen, the iodide is then oxidized to iodine. this makes it more reactive, and the iodine is attached to the active tyrosine units in thyroglobulin by the enzyme thyroid peroxidase. this forms the precursors of thyroid hormones monoiodotyrosine (mit), and diiodotyrosine (dit). when the follicular cells are stimulated by thyroid-stimulating hormone, the follicular cells reabsorb thyroglobulin from the follicular lumen. the iodinated tyrosines are cleaved, forming the thyroid hormones t4, t3, dit, mit, and traces of reverse triiodothyronine. t3 and t4 are released into the blood. the hormones secreted from the gland are about 80–90% t4 and about 10–20% t3. deiodinase enzymes in peripheral tissues remove the iodine from mit and dit and convert t4 to t3 and rt3. this is a major source of both rt3 (95%) and t3 (87%) in peripheral tissues. regulation the production of thyroxine and triiodothyronine is primarily regulated by thyroid-stimulating hormone (tsh), released by the anterior pituitary gland. tsh release in turn is stimulated by thyrotropin releasing hormone (trh), released in a pulsatile manner from the hypothalamus. the thyroid hormones provide negative feedback to the thyrotropes tsh and trh: when the thyroid hormones are high, tsh production is suppressed. this negative feedback also occurs when levels of tsh are high, causing trh production to be suppressed. trh is secreted at an increased rate in situations such as cold exposure in order to stimulate thermogenesis. in addition to being suppressed by the presence of thyroid hormones, tsh production is blunted by dopamine, somatostatin, and glucocorticoids. calcitonin main article: calcitonin the thyroid gland also produces the hormone calcitonin, which helps regulate blood calcium levels. parafollicular cells produce calcitonin in response to high blood calcium. calcitonin decreases the release of calcium from bone, by decreasing the activity of osteoclasts, cells which break down bone. bone is constantly reabsorbed by osteoclasts and created by osteoblasts, so calcitonin effectively stimulates movement of calcium into bone. the effects of calcitonin are opposite those of the parathyroid hormone (pth) produced in the parathyroid glands. however, calcitonin seems far less essential than pth, since calcium metabolism remains clinically normal after removal of the thyroid (thyroidectomy), but not the parathyroid glands. gene and protein expression further information: bioinformatics § gene and protein expression about 20,000 protein-coding genes are expressed in human cells: 70% of these genes are expressed in thyroid cells. two-hundred and fifty of these genes are more specifically expressed in the thyroid, and about 20 genes are highly thyroid specific. in the follicular cells, the proteins synthesized by these genes direct thyroid hormone synthesis—thyroglobulin, tpo, and iyd; while in the parafollicular c-cells, they direct calcitonin synthesis—calca, and calcb. clinical significance general practitioners, and internal medicine specialists play a role in identifying and monitoring the treatment of thyroid disease. endocrinologists and thyroidologists are thyroid specialists. thyroid surgeons or otolaryngologists are responsible for the surgical management of thyroid disease. hyperthyroidism main article: hyperthyroidism excessive production of the thyroid hormones is called hyperthyroidism. causes include graves' disease, toxic multinodular goitre, solitary thyroid adenoma, inflammation, and a pituitary adenoma which secretes excess tsh. another cause is excess iodine availability, either from excess ingestion, induced by the drug amiodarone, or following iodinated contrast imaging. hyperthyroidism often causes a variety of non-specific symptoms including weight loss, increased appetite, insomnia, decreased tolerance of heat, tremor, palpitations, anxiety and nervousness. in some cases it can cause chest pain, diarrhoea, hair loss and muscle weakness. such symptoms may be managed temporarily with drugs such as beta blockers. long-term management of hyperthyroidism may include drugs that suppress thyroid function such as propylthiouracil, carbimazole and methimazole. alternatively, radioactive iodine-131 can be used to destroy thyroid tissue: radioactive iodine is selectively taken up by thyroid cells, which over time destroys them. the chosen first-line treatment will depend on the individual and on the country where being treated. surgery to remove the thyroid can sometimes be performed as a transoral thyroidectomy, a minimally invasive procedure. surgery does however carry a risk of damage to the parathyroid glands and the recurrent laryngeal nerve, which innervates the vocal cords. if the entire thyroid gland is removed, hypothyroidism will inevitably result, and thyroid hormone substitutes will be needed. hypothyroidism main article: hypothyroidism an underactive thyroid gland results in hypothyroidism. typical symptoms are abnormal weight gain, tiredness, constipation, heavy menstrual bleeding, hair loss, cold intolerance, and a slow heart rate. iodine deficiency is the most common cause of hypothyroidism worldwide, and the autoimmune disease hashimoto's thyroiditis is the most common cause in the developed world. other causes include congenital abnormalities, diseases causing transient inflammation, surgical removal or radioablation of the thyroid, the drugs amiodarone and lithium, amyloidosis, and sarcoidosis. some forms of hypothyroidism can result in myxedema and severe cases can result in myxedema coma. hypothyroidism is managed with replacement of the thyroid hormones. this is usually given daily as an oral supplement, and may take a few weeks to become effective. some causes of hypothyroidism, such as postpartum thyroiditis and subacute thyroiditis may be transient and pass over time, and other causes such as iodine deficiency may be able to be rectified with dietary supplementation. graves' disease main article: graves' disease graves' disease is an autoimmune disorder that is the most common cause of hyperthyroidism. in graves' disease, for an unknown reason autoantibodies develop against the thyroid stimulating hormone receptor. these antibodies activate the receptor, leading to development of a goitre and symptoms of hyperthyroidism, such as heat intolerance, weight loss, diarrhoea and palpitations. occasionally such antibodies block but do not activate the receptor, leading to symptoms associated with hypothyroidism. in addition, gradual protrusion of the eyes may occur, called graves' ophthalmopathy, as may swelling of the front of the shins. graves' disease can be diagnosed by the presence of pathomnomonic features such as involvement of the eyes and shins, or isolation of autoantibodies, or by results of a radiolabelled uptake scan. graves' disease is treated with anti-thyroid drugs such as propylthiouracil, which decrease the production of thyroid hormones, but hold a high rate of relapse. if there is no involvement of the eyes, then use of radioactive isotopes to ablate the gland may be considered. surgical removal of the gland with subsequent thyroid hormone replacement may be considered, however this will not control symptoms associated with the eye or skin. nodules main article: thyroid nodule thyroid nodules are often found on the gland, with a prevalence of 4–7%. the majority of nodules do not cause any symptoms, thyroid hormone secretion is normal, and they are non-cancerous. non-cancerous cases include simple cysts, colloid nodules, and thyroid adenomas. malignant nodules, which only occur in about 5% of nodules, include follicular, papillary, medullary carcinomas and metastasis from other sites nodules are more likely in females, those who are exposed to radiation, and in those who are iodine deficient. when a nodule is present, thyroid function tests determine whether the nodule is secreting excess thyroid hormones, causing hyperthyroidism. when the thyroid function tests are normal, an ultrasound is often used to investigate the nodule, and provide information such as whether the nodule is fluid-filled or a solid mass, and whether the appearance is suggestive of a benign or malignant cancer. a needle aspiration biopsy may then be performed, and the sample undergoes cytology, in which the appearance of cells is viewed to determine whether they resemble normal or cancerous cells. the presence of multiple nodules is called a multinodular goitre; and if it is associated with hyperthyroidism, it is called a toxic multinodular goitre. goitre main article: goitre an enlarged thyroid gland is called a goitre. goitres are present in some form in about 5% of people, and are the result of a large number of causes, including iodine deficiency, autoimmune disease (both graves' disease and hashimoto's thyroiditis), infection, inflammation, and infiltrative disease such as sarcoidosis and amyloidosis. sometimes no cause can be found, a state called "simple goitre". some forms of goitre are associated with pain, whereas many do not cause any symptoms. enlarged goitres may extend beyond the normal position of the thyroid gland to below the sternum, around the airway or esophagus. goitres may be associated with hyperthyroidism or hypothyroidism, relating to the underlying cause of the goitre. thyroid function tests may be done to investigate the cause and effects of the goitre. the underlying cause of the goitre may be treated, however many goitres with no associated symptoms are simply monitored. inflammation main article: thyroiditis inflammation of the thyroid is called thyroiditis, and may cause symptoms of hyperthyroidism or hypothyroidism. two types of thyroiditis initially present with hyperthyroidism and are sometimes followed by a period of hypothyroidism – hashimoto's thyroiditis and postpartum thyroiditis. there are other disorders that cause inflammation of the thyroid, and these include subacute thyroiditis, acute thyroiditis, silent thyroiditis, riedel's thyroiditis and traumatic injury, including palpation thyroiditis. hashimoto's thyroiditis is an autoimmune disorder in which the thyroid gland is infiltrated by the lymphocytes b cell and t cells. these progressively destroy the thyroid gland. in this way, hasimoto's thyroiditis may have occurred insidiously, and only be noticed when thyroid hormone production decreases, causing symptoms of hypothyroidism. hashimoto's is more common in females than males, much more common after the age of 60, and has known genetic risk factors. also more common in individuals with hashimoto's thyroiditis are type 1 diabetes, pernicious anaemia, addison's disease vitiligo. postpartum thyroiditis occurs sometimes following childbirth. after delivery, the thyroid becomes inflamed and the condition initially presents with a period of hyperthyroidism followed by hypothyroidism and, usually, a return to normal function. the course of the illness takes place over several months, and is characterised by a painless goitre. antibodies against thyroid peroxidase can be found on testing. the inflammation usually resolves without treatment, although thyroid hormone replacement may be needed during the period of hypothyroidism. cancer main article: thyroid cancer the most common tumor affecting the thyroid is a benign adenoma, usually presenting as a painless mass in the neck. thyroid cancers are most often carcinomas, although cancer can occur in any tissue that the thyroid consists of, including cancer of c-cells and lymphomas. cancers from other sites also rarely lodge in the thyroid. radiation of the head and neck presents