The thyroid hormone is well known for controlling metabolism, growth, and many other body functions. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain a proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.
Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. 
Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching anterior pituitary.
TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nontropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nontropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation. 
TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP. The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions. The five steps of thyroid synthesis are below:
Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.
Heart: thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
Lungs: thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
Skeletal muscles: thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
Metabolism: thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
Growth during childhood: In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.
Physiological effects of thyroid hormones are listed below:
Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. 
Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. 
Hypothalamus releases thyrotropin-releasing hormone (TRH) that stimulates the secretion of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH through a negative feedback loop. As a result, T3 and T4 secretion, and iodine uptake are reduced. Other hormones, such as somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and exercise increase TRH release.
The initial tests of choice to screen for any thyroid abnormality are a TSH and free thyroxine (free T4) test. These determine whether the abnormality arises centrally from the thyroid gland (primary), peripherally from the pituitary (secondary), or hypothalamus (tertiary). In primary hypothyroidism is suspected, the thyroid gland is not releasing enough thyroid hormones. Therefore, TSH levels will be appropriately elevated, while free T4 levels will be lower. In primary hyperthyroidism, free T4 levels abnormally increased, and TSH levels will be appropriately decreased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis, respectively.
In pregnant women, thyroid-binding globulin production is increased because of estrogen and beta-human chorionic gonadotropin (beta-HCG). More free T4 will be bound to TGB, leading to increased production of T4. TSH levels and free T4 levels will normalize, and total T4 will increase. Therefore, laboratory values will show normal TSH, normal free T4, and elevated total T4. 
Hyperthyroidism: Disorders of the thyroid gland can result in excess T3 and T4 production along with the compensatory decrease of TSH. In addition, thyrotroph adenoma can produce unregulated TSH and can lead to increased T3 and T4 production. In some conditions, there is an ectopic production of thyroid hormone leading to increased thyroid hormones and compensatory TSH decrease.
Hypothyroidism: In primary hypothyroidism, decreased production of thyroid hormones by the thyroid gland causes a compensatory increase of TSH. Secondary hypothyroidism is caused by pituitary disorders causing decreased TSH release and decreased T3/T4 levels. Tertiary hypothyroidism is caused by hypothalamic disorders which result in decreased TRH levels, decreased TSH, and T3/T4 levels.
Two of the most common causes of hyperthyroidism and hyperthyroidism are below:
Graves disease is the most common cause of hyperthyroidism. It is an autoimmune disease caused by the production of TSH receptor antibodies that stimulate thyroid gland growth and thyroid hormone release. Patients will have abnormally increased T4 and T3 levels and a decrease in TSH. A positive TSH-receptor IgG immunoglobulin test confirms the diagnosis. Immunoglobulin G (IgG) against TSH-receptor leads to increased thyroid function and growth. Patients will often present with symptoms of hyperthyroidism and diffuse goiter. TSH-receptor antibodies can also activate orbital fibroblasts leading to fibroblast proliferation and differentiation to adipocytes. As a result, there is increased production of hyaluronic acid and glycosaminoglycan (GAG), leading to an increased volume of intraorbital fat and muscle tissue. It causes exophthalmos, lid retraction, and diplopia due to ocular motility problems. Pretibial myxedema is another finding in Graves' disease. It is due to the stimulation of dermal fibroblasts that leads to depositions of GAGs in the connective tissue. 70% of patients with Graves disease have elevated anti-TPO antibodies.
The most common cause of hypothyroidism in iodine-sufficient areas is Hashimoto Thyroiditis. It is caused by autoimmune-mediated destruction of the thyroid gland. CD8+ T-cells cause thyroid follicular cell death. The release of IFN-gamma by TH1 cells causes recruitment and activation of macrophages. During the early stage of the disease, the patient may develop a non-tender, symmetrical, and painless goiter. As inflammation continues, thyroid follicles are damaged and can rupture. When thyroid follicles rupture, the patient may be asymptomatic or can experience Hashitoxicosis (thyroid hormone from ruptured follicles, causing symptoms of hyperthyroidism). As the disease progresses, the thyroid gland may become normal-size or small, depending on the extent of fibrosis. As a result, the patient can develop the symptoms of hypothyroidism. In addition to cell-mediated destruction, anti-thyroid autoantibodies (anti-thyroglobulin and anti-TPO) are also produced leading to anti-body dependent cell-mediated cytotoxicity. Hashimoto thyroiditis is diagnosed via ultrasound, antibody detection, and thyroid function testing. Radioactive iodine uptake test and fine-needle aspiration can be performed to exclude malignancy.
Symptoms of Hypothyroidism
Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.
Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.
Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.
Symptoms related to decreased metabolic rate:
Symptoms from generalized myxedema:
Symptoms of hyperprolactinemia:
Symptoms of Hyperthyroidism
Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.
Conditions associated with hypothyroidism
Conditions associated with hyperthyroidism
Antithyroid drugs that work in the thyroid gland 
Antithyroid drugs that work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.
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