Thyroid Physiology Diagram

[Reginald Hanfy]

Thyroidstimulating hormone, also known as TSH, is a glycoprotein hormone produced by the anterior pituitary. It is the primary stimulus for thyroid hormone production by the thyroid gland. It also exerts growth effects on thyroid follicular cells leading to enlargement of the thyroid. The hypothalamic-pituitary axis regulates TSH release. Specifically, neurons in the hypothalamus release TRH, or thyroid-releasing hormone, which stimulates thyrotrophs of the anterior pituitary to secrete TSH. TSH, in turn, stimulates thyroid follicular cells to release thyroid hormones in the form of T3 or T4. Triiodothyronine, or T3, is the active form of thyroid hormone. Though it represents only 20% of the released hormone, the majority of T3 comes from the peripheral conversion of T4 to T3. Tetraiodothyronine, also known as thyroxine or T4, constitutes more than 80% of the secreted hormone. When released into the circulation, it forms T3 through the process of de-iodination. T4 and T3 can then exert negative feedback on the anterior pituitary with high levels of T3/T4 decreasing TSH secretion and low levels of T3/T4 increasing TSH release. In this review, we discuss the physiology, biochemistry, and clinical relevance of TSH.[1]

Primary thyroid disease refers to problems arising from the thyroid gland itself. In contrast, secondary thyroid disease refers to central problems arising from the anterior pituitary that indirectly affects thyroid function. A thyroid problem can exist in the form of hyperthyroidism or hypothyroidism. Hyperthyroidism occurs when there is excessive thyroid hormone synthesis or release. Hypothyroidism, on the other hand, happens due to inadequate thyroid hormone production.

In primary hyperthyroidism, the thyroid produces large amounts of T3 and T4, which, through negative feedback inhibition, suppress TSH secretion from the anterior pituitary. In primary hypothyroidism, the thyroid produces insufficient amounts of T3 and T4, which leads to loss of negative feedback inhibition, and increased production of TSH from the anterior pituitary. In secondary hyperthyroidism, the anterior pituitary produces large amounts of TSH, which, in turn, stimulate the thyroid follicular cells to secrete thyroid hormones in excessive amounts. On the other hand, if the anterior pituitary were to produce low levels of TSH, lack of stimulation of thyroid follicular cells causes T3 and T4 levels to go down, thus secondary hypothyroidism.

TSH is the first-line screening test for the majority of patients with a suspected thyroid problem. Together, with T3 and T4, it helps assess whether thyroid disease is primary or secondary. Thyroid function tests measure the levels of T3, T4, and TSH in the blood. They are critical not only for diagnosing thyroid problems but also in differentiating between a primary and a secondary cause of thyroid disease. A change in TSH that parallels T3 and T4 changes indicates a secondary problem originating in the anterior pituitary. In contrast, a TSH change that follows the opposite direction of T3 and T4 suggests a problem in the thyroid gland itself.[2][3][4]

TSH is a peptide hormone produced by the anterior pituitary. It consists of two chains: an alpha chain and a beta chain. It has a molecular mass of approximately 28,000 Da. The composition is very similar to other glycoprotein hormones made by the anterior pituitary. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (HCG) very much resemble TSH. Specifically, they all have the same alpha subunit as TSH, but different beta chains that confer biological specificity. Since TSH, LH, FSH, and HCG share the same alpha subunit, they all function through the same cyclic adenine monophosphate (cAMP) second messenger system. The cAMP second messenger system entails adenine monophosphate (AMP) conversion to cAMP. In addition to cAMP, TSH also activates the IP3 signaling cascade. The IP3 second messenger system involves calcium release from the sarcoplasmic reticulum. Both cAMP and IP3/Ca2+ cascades lead to downstream physiological effects that enhance thyroid hormone synthesis and thyroid gland growth.

The primary target of TSH is the thyroid gland. Specifically, TSH modulates the release of T3 and T4 from thyroid follicular cells. Around 80% of the thyroid hormone is released as T4. T4 is de-iodinated to T3, which is a more potent thyroid hormone. Even though only about 20% of T3 originates from the thyroid gland, 80% comes from peripheral conversion via a deiodinase. More than 99% of thyroid hormones bind to thyroid-binding globulin, prealbumin, and albumin, and only 1% circulates freely in the blood. Once T3 binds to its receptor in the nucleus, it activates DNA transcription, followed by mRNA translation, and new protein synthesis. These new proteins influence many organ systems, promoting growth as well as bone and central nervous system (CNS) maturation. T3 and T4 act on almost all cells in the body to increase the basal metabolic rate. Specifically, they increase the synthesis of Na?/K?-ATPase, leading to an increase in oxygen consumption and heat production. They also act on B1 receptors in the heart to increase heart rate and contractility through increasing the number of beta-1 receptors on the myocardium such that the myocardium is more sensitive to stimulation by the sympathetic nervous system. Thyroid hormones also activate metabolism, with an increase in glucose absorption, glycogenolysis, gluconeogenesis, lipolysis, and protein synthesis and degradation (net catabolic).[5]

TSH binds to and activates the TSH receptor (TSHR), which is a G-protein coupled receptor (GPCR) on the basolateral surface of thyroid follicular cells. TSHR is coupled to both Gs and Gq G-proteins, activating both the cAMP pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second messenger signaling cascades. The Gs pathway activates iodide uptake, thyroid hormone secretion, and gland growth and differentiation. The Gq pathway is rate-limiting for hormone synthesis by stimulating iodide organification. A gain in function mutation of the TSH receptor results in hyperthyroidism, while a loss in function mutation results in hypothyroidism.

Understanding the role of TSH in stimulating T3 and T4 secretion requires knowledge of the thyroid hormone synthesis pathway. The two main components of T3 and T4 are iodine and tyrosine. Iodine (I2) forms through oxidation of iodide (I-) after thyroid follicular cells actively take up iodide (I-) from the bloodstream against its concentration gradient. Tyrosine, on the other hand, comes from thyroglobulin, a tyrosine-rich protein synthesized by thyroid follicular cells. Following iodide uptake and oxidation, iodine binds tyrosine residues on thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Triiodothyronine, or T3, forms when an MIT mixes up with DIT. Likewise, the coupling of two DITs creates tetraiodothyronine (T4), or thyroxine. The process of iodide oxidation, thyroglobulin iodination, and MIT and DIT coupling is catalyzed by an enzyme called, thyroperoxidase. TSH stimulates thyroid hormone secretion through enhancing iodide uptake, thyroglobulin synthesis, and thyroperoxidase activity. Additionally, TSH also increases blood flow to the thyroid gland and stimulates hypertrophy and hyperplasia of thyroid follicular cells to exert growth effects on the thyroid gland.[6]

The hypothalamic-pituitary axis regulates TSH release through hypothalamic neurons that secrete thyroid releasing hormone (TRH), a hormone that stimulates thyrotrophs in the anterior pituitary to secrete TSH. TSH, in turn, stimulates thyroid follicular cells to release thyroxine or T4 (80%), and triiodothyronine or T3 (20%). Somatostatin, on the other hand, is another hormone produced by the hypothalamus that inhibits the release of TSH from the anterior pituitary. When T4 enters the circulation, it gets converted to T3 through the process of deiodination. T4 and T3 can then exert negative feedback on TSH levels (high levels of T3/T4 decrease TSH release from the anterior pituitary, while low levels of T3/T4 increase TSH release). T3 is the predominant inhibitor of TSH secretion. Because TSH secretion is so sensitive to minor changes in free T4 through this negative feedback loop, abnormal TSH levels are detected earlier than those of free T4 in hypothyroidism and hyperthyroidism. There is a log-linear relationship between T3/T4 and TSH, and minor changes in T3/T4 lead to significant changes in TSH.

TSH is the first-line screening test for both hypothyroidism and hyperthyroidism since changes in TSH occur earlier that changes in T3/T4. If values are outside the range of 0.4 to 4.5 milliunits per liter (mU/L), measuring T3 and T4 should follow. However, TSH is always the best first test because it is more reliable than plasma T3/T4 levels, which tend to fluctuate. In primary hypothyroidism, TSH levels are elevated due to the loss of negative inhibition on the anterior pituitary. In contrast, in primary hyperthyroidism, TSH levels go down.

Another relevant test when it comes to thyroid disease is thyroid-stimulating immunoglobulin (TSI). The test is diagnostic for a condition called Grave's disease. As discussed later, Grave's disease is an autoimmune disease characterized by the presence of autoantibodies in the blood that exert TSH-like effects. The antibodies stimulate TSHR on thyroid follicular cells leading to uncontrolled thyroid hormone synthesis and release. The test detects the presence of thyroid-stimulating antibodies (TSIs) in the blood.[7]

Hyperthyroidism is a condition characterized by excessive secretion of thyroid hormones. A variety of medical conditions lead to hyperthyroidism, including Graves' disease, thyroid neoplasm, thyroid adenomas, excess TSH secretion, or exogenous T3 or T4 administration. Symptoms of hyperthyroidism include increased basal metabolic rate, weight loss, increased appetite, sweating, tremors, heat sensitivity, irritability, diarrhea, and insomnia. In primary hyperthyroidism, as in the case of a thyroid adenoma, TSH levels tend to decrease due to negative feedback inhibition exerted on the anterior pituitary by T3 and T4. In secondary hyperthyroidism, as in the case of a TSH or TRH secreting tumor, both TSH and T3/T4 levels increase. [8][9]

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