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You are watching: Thyroid hormone exerts its influence by

StatPearls . Treasure Island (FL): StatPearls Publishing; 2021 Jan-.


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Physiology, Thyroid Hormone

Muhammad A. Shahid; Muhammad A. Ashraf; Sandeep Sharma.

Author Information

Introduction

The thyroid hormone is famous for regulating metabolism, growth, and also many other bodily functions. The thyroid gland, anterior pituitary gland, and also hypothalamus consist of a self-regulatory circuit dubbed the hypothalamic-pituitary-thyroid axis. The main hormones developed by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) indigenous the hypothalamus, thyroid-stimulating hormone (TSH) indigenous the anterior pituitary gland, and T4 work-related in synchronous harmony come maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by one underactive thyroid gland, commonly manifests together bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism led to by enhanced thyroid gland function manifests together weight loss, heat intolerance, diarrhea, good tremor, and muscle weakness.

Iodine is an essential trace element soaked up in the little intestine. It is an integral component of T3 and T4. Resources of iodine encompass iodized table salt, seafood, seaweed, and vegetables. Diminished iodine entry can reason iodine deficiency and also decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism.<1><2><3>


Cellular

Regulation the thyroid hormone starts in ~ the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) right into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary come the relax of thyroid-stimulating hormone (TSH). TRH is a peptide hormone produced by the cabinet bodies in the periventricular nucleus (PVN) the the hypothalamus. These cabinet bodies project their neurosecretory neurons under to the hypophyseal portal circulation, wherein TRH deserve to concentrate before reaching the anterior pituitary.

TRH is a tropical hormone, an interpretation that it indirect affects cells by stimulating other endocrine glands first. It binding to the TRH receptors on the anterior pituitary gland, leading to a signal cascade mediated by a G-protein combination receptor. Activation the Gq protein leads to the activation that 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 also transcription of TSH. TRH likewise has a non-tropic impact on the pituitary gland v the hypothalamic-pituitary-prolactin axis. Together a non-tropic hormone, TRH straight stimulates lactotropic cells in the anterior pituitary to develop prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and also estrogen can likewise stimulate prolactin release. Prolactin can reason breast tissue growth and lactation.<4>

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) ~ above the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and also its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The raised cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions. The five steps the thyroid synthesis room below:


Synthesis the Thyroglobulin: Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and also it is a precursor protein save in the lumen the follicles. The is created in the turbulent endoplasmic reticulum. Golgi apparatus pack it right into the vesicles, and then it enters the follicular lumen with exocytosis.
Iodide uptake: Protein kinase A phosphorylation causes increased task of basolateral Na+-I- symporters, pushed by Na+-K+-ATPase, to bring iodide indigenous the circulation right into the thyrocytes. Iodide then diffuses indigenous the basolateral side to the apex that the cell, wherein it is transported right into the colloid with the pendrin transporter.
Iodination that thyroglobulin: Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and also coupling reaction.
Oxidation: TPO supplies hydrogen peroxide to oxidize iodide (I-) come iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide because that TPO.
Organification: TPO web links tyrosine residual water of thyroglobulin protein v I2. It generates monoiodotyrosine (MIT) and also diiodotyrosine (DIT). MIT has a single tyrosine residue v iodine, and also DIT has actually two tyrosine residues through iodine.
Coupling reaction: TPO combine iodinated tyrosine residues to do triiodothyronine (T3) and also tetraiodothyronine (T4). MIT and DIT sign up with to form T3, and also two DIT molecules form T4.

Organ solution Involved

Thyroid hormone affects virtually every organ mechanism in the body, consisting of the heart, CNS, autonomic worried system, bone, GI, and metabolism. In general, as soon as the thyroid hormone binding to that is intranuclear receptor, that activates the gene for enhancing metabolic rate and thermogenesis. Enhancing metabolic rate entails increased oxygen and also energy consumption.

Heart: thyroid hormones have actually a permissive result on catecholamines. It boosts the expression the beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.

Lungs: thyroid hormones stimulate the respiratory centers and also lead to raised oxygenation since of enhanced perfusion.

Skeletal muscles: thyroid hormones cause increased advance of kind II muscle fibers. These room fast-twitch muscle fibers qualified of rapid and powerful contractions.

Metabolism: thyroid hormone boosts the basal metabolic rate. It rises the gene expression that Na+/K+ ATPase in different tissues leading to enhanced oxygen consumption, respiration rate, and also body temperature. Depending upon the metabolic status, it have the right to induce lipolysis or lipid synthesis. Thyroid hormone stimulate the line of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of protein in high doses. Thyroid hormones do not adjust the blood glucose level, yet they can reason 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. That induces chondrocytes, osteoblasts, and also osteoclasts. Thyroid hormone additionally helps with mind maturation by axonal growth and the formation of the myelin sheath.<7>


Mechanism

Thyroid hormones are lipophilic and also circulate bound to the move proteins. Just a fraction (approximately 0.2%) of the thyroid hormone (free T4) is unbound and also active. Transporter proteins encompass thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) the the T4, and also transthyretin transports thyroxine and retinol. Once it reaches its target site, T3 and T4 can dissociate from your binding protein to enter cells one of two people by diffusion or carrier-mediated transport. Receptors for T3 tie are already bound come the DNA in the nucleus prior to the ligand binding. T3 or T4 then tie to atom alpha or beta receptor in the corresponding tissue and also cause activation of transcription factors leading to the activation of details genes and cell-specific responses. Thyroid hormones room degraded in the liver via sulfation and glucuronidation and also excreted in the bile.<8>

Thyroid receptors are transcription components that have the right to bind to both T3 and T4. However, they have actually a much higher affinity because that T3. Together a result, T4 is reasonably inactive. Deiodinases convert T4 to energetic T3 or inactive turning back T3 (rT3). There room three types of deiodinases: type I, II, and also III. Form I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and also thyroid glands. Form III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 transform T4 to the active type T3, and DIO3 converts T4 into inactive form rT3.<8>


Related Testing

Hypothalamus releases thyrotropin-releasing hormone (TRH) the stimulates the cheap of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH with a an unfavorable feedback loop. Together a result, T3 and also T4 secretion and iodine uptake room reduced. Various other hormones, such together somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and also exercise increase TRH release.

The initial exam of choice to display for any kind of thyroid abnormality room a TSH and cost-free thyroxine (free T4) test. This determine whether the abnormality arises centrally native the thyroid gland (primary), peripherally native the pituitary (secondary), or hypothalamus (tertiary). In main hypothyroidism is suspected, the thyroid gland is no releasing sufficient thyroid hormones. Therefore, TSH levels will be as necessary elevated, while free T4 levels will certainly be lower. In major hyperthyroidism, complimentary T4 level abnormally increased, and TSH levels will be appropriately decreased. Various other lab exam such together TSH receptor antibodies or antitoxin to thyroid peroxidase deserve to help aid in diagnosing Graves condition or Hashimoto thyroiditis, respectively.<9>

In pregnant women, thyroid-binding globulin production is increased due to the fact that of estrogen and beta-human reasonable gonadotropin (beta-HCG). More totally free T4 will certainly be bound to TGB, top to increased production the T4. TSH level and cost-free T4 levels will certainly normalize, and also total T4 will increase. Therefore, laboratory worths will display normal TSH, normal totally free T4, and also elevated complete T4.<10>


Pathophysiology

Hyperthyroidism: disorders of the thyroid gland can an outcome in overabundance T3 and also T4 production along with the compensatory diminish of TSH. In addition, thyrotroph adenoma can develop unregulated TSH and can lead to increased T3 and also T4 production. Over there is an ectopic production of thyroid hormone in some conditions, top to enhanced thyroid hormones and compensatory TSH decrease.

Hypothyroidism: In major hypothyroidism, diminished production the thyroid hormone by the thyroid gland causes a compensatory rise of TSH. Second hypothyroidism is resulted in by pituitary obstacle causing diminished TSH release and also decreased T3/T4 levels. Tertiary hypothyroidism is brought about by hypothalamic disorders, resulting in diminished TRH levels, decreased TSH, and T3/T4 levels.

Two that the most common causes of hyperthyroidism and also hyperthyroidism room below:

Graves Disease

Graves an illness is the most common reason of hyperthyroidism. That is one autoimmune condition caused by the production of TSH receptor antibodies the stimulate thyroid gland growth and thyroid hormone release. Patient will have actually abnormally increased T4 and T3 levels and a decrease in TSH. A positive TSH-receptor IgG immunoglobulin check confirms the diagnosis. Immunoglobulin G (IgG) versus TSH-receptor leads to raised thyroid duty and growth. Patients will certainly often present with symptoms of hyperthyroidism and diffuse goiter. TSH-receptor antibodies can also activate orbit fibroblasts leading to fibroblast proliferation and also differentiation to adipocytes. As a result, over there is boosted production that hyaluronic acid and glycosaminoglycan (GAG), causing an increased volume the intraorbital fat and also muscle tissue. It reasons exophthalmos, lid retraction, and also diplopia due to ocular motility problems. Pretibial myxedema is another finding in Graves" disease. That is because of the stimulation of dermal fibroblasts that leads to depositions the GAGs in the connective tissue. 70% the patients through Graves an illness have elevated anti-TPO antibodies.

Hashimoto Thyroiditis

The most common reason of hypothyroidism in iodine-sufficient areas is Hashimoto Thyroiditis. That is led to by autoimmune-mediated destruction of the thyroid gland. CD8+ T-cells reason thyroid follicular cabinet death. The relax of IFN-gamma by TH1 cells reasons recruitment and also activation that macrophages. Throughout the beforehand stage the the disease, the patient may construct a non-tender, symmetrical, and painless goiter. Together inflammation continues, thyroid follicles space damaged and can rupture. When thyroid follicles rupture, the patient may be asymptomatic or deserve to experience Hashitoxicosis (thyroid hormone native ruptured follicles, bring about symptoms of hyperthyroidism). As the condition progresses, the thyroid gland may become normal-size or small, depending upon the degree of fibrosis. Together a result, the patient can develop the symptom of hypothyroidism. In enhancement to cell-mediated destruction, anti-thyroid autoantibodies (anti-thyroglobulin and also anti-TPO) are also produced, bring about antibody-dependent cell-mediated cytotoxicity. Hashimoto thyroiditis is diagnosed via ultrasound, antibody detection, and thyroid duty testing. Radioactive iodine uptake test and fine-needle aspiration can be performed come exclude malignancy.


Clinical Significance

Symptoms the Hypothyroidism

Generalized decreased basal metabolic price can existing as apathy, slowed cognition, skin dryness, alopecia, boosted low-density lipoproteins, and also increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting v apathy and slowed cognition. Hypothyroidism deserve to decrease sympathetic task leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and also decreased cardiac output because of lessened transcription that sarcolemmal genes.

Hyperprolactinemia deserve to be led to by hypothyroidism. Thyrotropin-releasing hormone (TRH) native the hypothalamus stimulates prolactin and TSH release. Prolactin release deserve to suppress testosterone, LH, FSH, and also GnRH release. Prolactin can also cause chest tissue growth.

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Patients with hypothyroidism may current with myxedema resulted in by reduced clearance of facility glycosaminoglycans and hyaluronic mountain from the reticular great of the dermis. Initially, the nonpitting edema is pretibial. Together the state the hypothyroidism continues, patients can build generalized edema.