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What Function Is Regulated By Thyroid Hormones

Overview Of The Thyroid Gland

Thyroid Gland: Thyroid Hormone Function

, MD, MS, David Geffen School of Medicine at UCLA

The thyroid is a small gland, measuring about 2 inches across, that lies just under the skin below the Adams apple in the neck. The two halves of the gland are connected in the middle , giving the thyroid gland the shape of a bow tie. Normally, the thyroid gland cannot be seen and can barely be felt. If it becomes enlarged, doctors can feel it easily, and a prominent bulge may appear below or to the sides of the Adams apple.

The thyroid gland secretes thyroid hormones, which control the speed at which the bodys chemical functions proceed . Thyroid hormones influence the metabolic rate in two ways:

    Thyroid hormones affect many vital body functions, such as the heart rate, the rate at which calories are burned, skin maintenance, growth, heat production, fertility, and digestion.

    Future Directions And Conclusions

    Monodeiodination is quantitatively the most important pathway of TH activation. Within peripheral tissue, multiple pathways modulate TH availability. These pathways govern the action and regulation of deiodinase expression, the action of TH transporters, and the expression and crosstalk of TH receptors with multiple partners. This intricate network of TH modifiers increases the sensitivity and the speed of responses to changes induced in the internal and external environment by the thyroid signal. The price to be paid for this is an intricate regulation of each component in time and space. Given the vast spectrum of metabolic body functions regulated by the TH signal, the deiodinases represent a powerful tool with which to modulate cellular metabolism in specific tissues without perturbing systemic levels of THs. Consequently, the development of drugs that target deiodinase action is the next challenge in this field. Extensive work is still required to delineate the kinetics and regulation of the deiodinase enzymes in specific tissues to understand the full spectrum of their biological roles. Thus, pharmacological research is poised to develop deiodinase modulators aimed at driving specific metabolic outcomes. Targeting tissue-specific TH actions may result in novel and safe therapeutic options for metabolic dysfunctions.

    How Does The Thyroid Gland Work

    The thyroid gland is a vital hormone gland: It plays a major role in the metabolism, growth and development of the human body. It helps to regulate many body functions by constantly releasing a steady amount of thyroid hormones into the bloodstream. If the body needs more energy in certain situations for instance, if it is growing or cold, or during pregnancy the thyroid gland produces more hormones.

    This organ is found at the front of the neck, under the voice box. It is butterfly-shaped: The two side lobes lie against and around the windpipe , and are connected at the front by a narrow strip of tissue.

    The thyroid weighs between 20 and 60 grams on average. It is surrounded by two fibrous capsules. The outer capsule is connected to the voice box muscles and many important vessels and nerves. There is loose connective tissue between the inner and the outer capsule, so the thyroid can move and change its position when we swallow.

    The thyroid tissue itself consists of a lot of small individual lobules that are enclosed in thin layers of connective tissue. These lobules contain a great number of small vesicles called follicles which store thyroid hormones in the form of little droplets.

    Thyroid gland cells

    The thyroid gland produces three hormones:

    • Triiodothyronine, also known as T3
    • Tetraiodothyronine, also called thyroxine or T4
    • Calcitonin

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    Anatomy Of The Thyroid Gland

    The thyroid gland is a butterfly-shaped organ and is composed of two cone-like lobes or wings, lobus dexter and lobus sinister , connected via the isthmus. The organ is situated on the anterior side of the neck, lying against and around the larynx and trachea, reaching posteriorly the oesophagus and carotid sheath.

    It starts cranially at the oblique line on the thyroid cartilage , and extends inferiorly to approximately the fifth or sixth tracheal ring. It is difficult to demarcate the glands upper and lower border with vertebral levels because it moves in position in relation to these structures during swallowing.

    A Regulation Of Cholesterol Synthesis

    Thyroid Hormone Regulation

    TH regulates cholesterol synthesis through multiple mechanisms. A major pathway is TH stimulation of transcription of the LDL-R gene resulting in increased uptake of cholesterol and enhanced cholesterol synthesis . This has been a major pathway of T4-mediated cholesterol lowering after T4 treatment of patients with hypothyroidism . Another regulator of the LDL-R gene is the sterol response element binding protein -2 . SREBP-2 is a member of a family of transcription factors that regulate glucose metabolism, fatty acid synthesis, and cholesterol metabolism. Specifically, TH induces SREBP-2 gene expression that in turn modulates LDL-R expression. In hypothyroid rats, SREBP-2 mRNA is suppressed, but this is reversed when T3 levels are restored . This nuclear coregulation is further highlighted by the fact that several genes have a tandem arrangement of the TRE and SREBP response element . Other nuclear hormone receptors, such as PPAR, have opposing effects on LDL and cholesterol synthesis , which underscore the role of nuclear crosstalk in TH regulation of metabolism . The isoform-specific induction of LDL-R highlights the role of T3 action in the liver.

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    Clinical Manifestation Of Th Signaling Related Mutations In Humans

    The developing skeleton is sensitive to thyroid status and childhood hypothyroidism is characterized by growth retardation, delayed bone age and short stature, whereas juvenile thyrotoxicosis accelerates growth and advances bone age but results in persistent short stature due to premature fusion of the epiphyses . A loss of function mutation of the TSH -subunit results in TSH deficiency and congenital hypothyroidism. Two affected siblings received TH replacement from birth but despite the lifelong absence of TSH, their skeletal development and bone mineral density were normal . These findings suggest that TSH is not required for normal skeletal development and growth. TSHR mutations result in wide spectrum of clinical manifestations ranging from mild to severe hypothyroidism and hyperthyroidism . Up to this date more than 40 kinds of loss of function mutations in the TSHR gene have been reported as the causative defect in congenital hypothyroidism . By contrast, gain of function mutations in the TSHR gene were identified in familial non-autoimmune hyperthyroidism or sporadic non-autoimmune hyperthyroidism .

    Table 2 Clinical manifestation of TH signaling related mutations in humans

    A Thyroid Hormone Receptor Nuclear Receptor Partners And Response Coregulators

    1. Thyroid receptor isoforms

    TH action is exerted primarily via the nuclear TR, a member of the superfamily of hormone-responsive nuclear transcription factors that share a similar structure and mechanism of action . The structure of the nuclear receptors, such as TR, includes a zinc finger motif DNA binding domain and a COOH-terminal domain that mediates ligand interactions as well as binding of coactivators and corepressors . The function of the amino terminus varies among nuclear receptors, but for TR has minimal functional significance. There are two primary isoforms of TR, and , which are differentially expressed developmentally and in adult tissues . Both TR and undergo posttranslational modification by sumoylation, which is essential for positive and negative gene regulation by TH, including genes important for metabolic regulation . Sumoylation of PPAR is essential for adipogenesis in a SUMO1 gene knockout mouse model . TR sumoylation may similarly impact metabolic genes directly regulated by TR and genes regulated by TR crosstalk with other nuclear receptors.

    2. Retinoid X receptor

    3. Nuclear receptor coregulators

    4. Resistance to TH

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    Mechanism Of Action And Physiologic Effects Of Thyroid Hormones

    Thyroid Hormone Receptors and Mechanism of Action

    Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones.

    Thyroid hormones enter cells through membrane transporter proteins. A number of plasma membrane transporters have been identified, some of which require ATP hydrolysis the relative importance of different carrier systems is not yet clear and may differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes.

    For the purpose of illustration, consider one mechanism by which thyroid hormones increase the strength of contraction of the heart. Cardiac contractility depends, in part, on the relative ratio of different types of myosin proteins in cardiac muscle. Transcription of some myosin genes is stimulated by thyroid hormones, while transcription of others in inhibited. The net effect is to alter the ratio toward increased contractility.

    For additional details on mechanism of action and how these receptors interact with other transcription factors, examine the section Thyroid Hormone Receptors.

    Physiologic Effects of Thyroid Hormones

    Thyroid Disease States

    Regulation Of Th Synthesis

    Hypothalamic Pituitary Thyroid Axis (regulation, TRH, TSH, thyroid hormones T3 and T4)

    The release of T3 and T4 from the thyroid gland is regulated by thyroid-stimulating hormone . As shown in Figure 17.4.2, low blood levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone from the hypothalamus, which triggers secretion of TSH from the anterior pituitary. In turn, TSH stimulates the thyroid gland to secrete T3 and T4. The levels of TRH, TSH, T3, and T4 are regulated by a negative feedback system in which increasing levels of T3 and T4 decrease the production and secretion of TSH.

    Figure 17.4.2 Classic Negative Feedback Loop:

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    How Can I Promote The Health Of The Thyroid Gland

    Iodine is most essential to maintain a healthy thyroid. Iodine is the critical ingredient for the production of thyroid hormones. We dont need a lot of iodine, it is said that one teaspoon of iodine is enough for a lifetime. Nonetheless, the daily and constant supply of this micronutrient is important. Too much iodine at once is counter-productive and causes your thyroid to produce less hormones. The best way to get your daily dose of iodine is through eating healthy foods like seafood and dairy products. In addition, iodized salt is a good source and you can use it to season your food. Nowadays, iodine is added to salt to combat goitres .

    Spotlight On Aging: Thyroid Gland Changes In Older People

    Aging itself has only minor effects on the thyroid gland and thyroid hormones. As people get older, the thyroid gland shrinks and shifts lower in the neck. The level of the thyroid hormone triiodothyronine may fall slightly, but the speed of vital functions changes very little. However, thyroid disorders become more common with aging.

    Disorders that affect thyroid function, particularly hyperthyroidism and hypothyroidism, can be thought of as great masqueraders in older people. These disorders often cause symptoms that are easily mistaken for symptoms of other conditions or even as signs of getting old.

    Increased or decreased thyroid function can dramatically worsen the way an older person feels and can greatly diminish the ability to carry out daily activities. For these reasons, the great masqueraders must be unmasked and recognized for what they are so that they can be effectively treated.

    Screening older people for hyperthyroidism and hypothyroidism is helpful. Some experts recommend measuring the level of thyroid-stimulating hormone in the blood in people over 65 every 5 years.

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    Which Hormones Does My Thyroid Gland Produce

    The thyroid gland produces thyroxine , which is a relatively inactive prohormone. The highly active hormone is triiodothyronine . Collectively, thyroxine and triiodothyronine are referred to as the thyroid hormones. The thyroid gland produces just 20% of the high active T3, but it produces 80% of the prohormone T4. Once secreted by the thyroid, specific enzymes in other tissues like the liver or kidneys may transform T4 in to the active hormone T3.

    In addition, there are other hormone-producing cells within the thyroid gland called C-cells. These cells produce calcitonin. Calcitonin plays a role in regulating calcium and phosphate levels in the blood, which is important for your bone health and maintenance.

    Hormone Imbalances: Overactive And Underactive Thyroid Gland

    17.4 The Thyroid Gland  Anatomy &  Physiology

    An overactive thyroid occurs if the thyroid gland makes too many hormones. An underactive thyroid is where the gland doesnt make enough hormones. Both of these imbalances can lead to a great number of symptoms.

    The thyroid gland may grow in size too. Sometimes the whole thyroid gland becomes enlarged , and sometimes individual lumps called nodules grow in the gland . A special examination, known as thyroid scintigraphy, can be used to see whether these nodules are producing abnormal amounts of hormones. If they make more hormones than the rest of the thyroid tissue, they are called hot nodules. If they make less, they are called cold nodules.

    In most cases, an enlarged thyroid or nodules arent caused by anything serious. They are only rarely cancer. But its still important to see a doctor if you notice any changes in your thyroid gland.

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    Food Availability Adjusts T3 Production And Controls Th Signaling

    In humans and other mammals, food availability is a key factor for stimulation of the thyroid system, ensuring coupling between caloric intake and TH signaling . Default thyroid activity, in the absence of food, is low, along with low circulating TH levels and a slow rate of energy expenditure. Once caloric intake is initiated, thyroidal activity is accelerated and circulating TH levels increase for example, this is seen in patients recovering from anorexia nervosa . In such patients, weight gain and elevation in serum T3 are closely associated with acceleration in energy expenditure . These mechanisms are largely driven by the hypothalamus, based on molecules that signal nutritional status, for example, leptin and insulin .

    Dio2 expression in the cerebral cortex is not modified by fasting or refeeding, indicating that Dio2 regulation by nutrient availability is not universal, likely occurring in tissues where the metabolic pathways are responsive to T3 and insulin such as BAT, SKM, and neonatal liver . Thus, the balance between PI3KmTORC2AKT and Foxo1 signaling in metabolically relevant tissues should provide nutritional input and fine-tuning to the regulation of circulating levels of T3 and T3-dependent processes.

    How The Body Adjusts Thyroid Hormones

    The body has a complex mechanism for adjusting the level of thyroid hormones. First, the hypothalamus, located just above the pituitary gland in the brain, secretes thyrotropin-releasing hormone, which causes the pituitary gland to produce thyroid-stimulating hormone . Just as the name suggests, TSH stimulates the thyroid gland to produce thyroid hormones. The pituitary gland slows or speeds the release of TSH, depending on whether the levels of thyroid hormones circulating in the blood are getting too high or too low.

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    Functions Of T3 And T4

    These hormones are essential to the growth of the body. The T3 and T4 hormones act on almost every cell, increasing the metabolic rate, affecting protein synthesis, and regulating bone growth. Too much or too little of these hormones can greatly affect various functions in the body which can cause ill effects or symptoms.

    Low Levels Of Tsh Hyperthyroidism

    Thyroid Gland Structure Hormones Functions and Regulation

    This indicates that the thyroid gland is hyperactive and is producing high levels of hormones. The condition is known as hyperthyroidism. People suffering from hyperthyroidism tend to lose weight, experience anxiety or palpitations, and feel very hot. The patients have a slightly enlarged thyroid gland. Medications are provided to control the increased and decreased levels of TSH. If not treated it might even turn serious. The symptoms of this disease become more apparent when the level of hyperthyroidism in the body increases and is associated with the increase in the metabolic rate of the body. However, there are a few causes which can lead to the condition as listed below:

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    B Insulin Production And Action

    Several studies have linked thyroid hormone action with pancreatic islet cell development and function. Pancreatic islets contain TR1 and TR1 which are important for normal islet development . T3 acts by stimulating the islet transcription factor Mafa. T3 is required for the transition of islets to glucose-responsive insulin-secreting cells. In pancreatic islet cells studied in culture, T3 and TR promote proliferation . Inactivation of D2 gene is associated with insulin resistance and diet-induced obesity . Thyroid hormone acts to impair glucose-stimulated insulin release, despite increased islet glucose utilization and oxidation. Hyperthyroidism and high-fat feeding result in significant impairment of islet function . In contrast, physiological T3 treatment prevents streptozocin-induced islet deterioration and maintains islet structure, size, and consistency . T3 induces these anti-apoptotic effects via nongenomic activation of the AKT signaling pathway.

    High Levels Of Tsh Hypothyroidism

    If a person has TSH levels more than normal, it means that he has an underactive thyroid gland. This condition is known as hypothyroidism in which the thyroid gland does not produce enough hormones. In this condition, the thyroid gland enlarges leading to goitre. The person may feel lethargic, cold and puts on weight. Patients suffering from this condition, show symptoms that are linked to slow metabolic rate. The condition may not be prominent in the initial stages, but over time, if left untreated, it can lead to several related health issues such as joints pain, infertility, obesity and even heart diseases.

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    Where Is My Thyroid Gland

    The thyroid gland is located at the front of the neck just below the Adam’s apple . It is butterfly-shaped and consists of two lobes located either side of the windpipe . A normal thyroid gland is not usually outwardly visible or able to be felt if finger pressure is applied to the neck.

    Diagram showing the location of the thyroid gland in the neck. It has two lobes and sits in front of the windpipe . The voice box sits just above the thyroid.

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