Thyroid Hormones

The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland. Thyroid-stimulating hormone is regulated by thyroid-releasing hormone (TRH; which is stimulatory) and somatostatin (which is inhibitory). Both of these hormones are produced by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus. T3 is far more active than T4, so most T4 is converted to T3 in the periphery (e.g., liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver). T3 helps to maintain normal cellular metabolism, oxygen consumption, energy levels, heart rate, thermoregulation, bowel movements, mental health, and neurologic function. Abnormalities in thyroid hormone levels can lead to hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism and hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview released by the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland

The primary hormones released from the thyroid include:

  • The thyroid hormones, triiodothyronine (T3) and thyroxine (T4):
    • Act on most cells/tissues in the body
    • Stimulate metabolism and oxygen consumption → primary regulators of body metabolism
    • Increase circulation and respiration
    • Promote nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System and skeletal development
  • Calcitonin: 
    • Produced by C cells in the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland
    • Works to ↓ Ca2+ serum levels, opposing the action of parathyroid hormone (PTH)
    • In bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones: stimulates osteoblasts → promotes calcium deposition and ossification
    • In kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: stimulates phosphate reabsorption → ↑ ossification

The hypothalamic-pituitary-thyroid (HPT) axis

Release of T3 and T4 is regulated by hormones secreted by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland. This complex interaction is known as the HPT axis:

  • Hypothalamus secretes:
    • Thyrotropin-releasing hormone (TRH; stimulatory) 
    • Somatostatin (inhibitory)
  • TRH stimulates thyrotropes in the anterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland to release TSH.
  • Thyroid-stimulating hormone (TSH) stimulates the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland to release T3 and T4
  • T3 and T4:
    • Stimulate metabolism throughout the body (their primary physiologic effect)
    • Feedback within the HPT axis:
      • Inhibit the release of TSH and TRH 
      • Stimulate the release of somatostatin 
  • Laboratory evaluation of the HPT axis:
    • When free T3 or T4 is abnormally ↑ → TSH will be low
    • When free T3 or T4 is abnormally ↓ → TSH will be high
Hypothalamic-pituitary-thyroid axis

Hypothalamic-pituitary-thyroid axis and the negative feedback loops

Image by Lecturio.

Thyroid Hormone Synthesis and Transportation

Synthesis

  • The thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland consists of thyroid follicular cells wrapped around colloid.
  • Components required to make thyroid hormones:
    • Iodine (I2): must be obtained from the diet
    • Thyroglobulin (Tg): produced in the thyroid follicular cells 
  • Iodide (I) is taken into the thyroid follicular cells by the sodium iodide symporter (NIS).
  • Iodide and Tg are moved into the colloid:
    • Iodide is secreted through pendrin channels and oxidized to form I2 (the form that can be bound to Tg).
    • Tg is exocytosed.
  • Thyroid peroxidase (TPO): combines I2 and Tg via iodination to form thyroid hormone intermediates
    • Mono-iodotyrosine (MIT; “T1”)
    • Di-iodotyrosine (DIT; “T2”) 
  • TPO then further combines these intermediates via a process called conjugation to make T3 and T4:
    • MIT + DITT3 
    • DIT + DIT → T4 
  • T3 and T4 are endocytosed into the follicular cells, cleaved by lysosomes, and secreted into the blood.
  • T4 activation:
    • Active (free) T3 is 10× stronger than active (free) T4.
    • Most T4 is converted to T3 by the peripheral enzyme 5’/3’ mono-deiodinase.
    • Some T4 is converted to reverse T3 (rT3) (an inactive metabolite).
Synthesis of thyroid hormones

Steps for synthesis of thyroid hormones:
DIT: di-iodotyrosine
MIT: mono-iodotyrosine
NIS: sodium iodide symporter
rT3: reverse triiodothyronine
TPO: thyroid peroxidase

Image by Lecturio.

Transportation

  • T3 and T4 are hydrophobic/lipophilic (can cross cell membranes → receptors are intracellular). 
  • Approximately 99% of T3 and T4 are protein-bound for transport within the blood by:
    • Thyroid-binding globulin (TBG) (primary binder)
    • Transthyretin
    • Albumin
  • Protein-bound hormones are inactive, serving as a reservoir.
  • Free and bound forms are in an equilibrium → levels of free hormone remain fairly constant

Physiologic Effects of the Thyroid Hormones

  • Within the cell, T3 binds to the thyroid hormone receptor (THR).
  • T3–THR complex binds to thyroid response elements (TREs) within DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure →  stimulates transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription/ translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation of a number of proteins including:
    • Na+/K+ pump
    • Gluconeogenic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Respiratory enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Myosin heavy chains
    • β-adrenergic receptors
  • These proteins generally all:
    • ↑ Cellular metabolism
    • ↑ Cellular oxygen consumption
    • ↑ Cellular glucose
    • ↑ Circulation and respiration
    • Promote nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System and skeletal development
  • Clinically, these hormones help maintain normal:
    • Energy levels
    • Weight
    • Thermoregulation
    • Heart rates
    • Bowel movements
    • Mood
Peripheral conversion of t4 and t3

Peripheral conversion of T4 and T3:
Thyroid hormones exert their greatest influence over transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription as T3.

Image by Lecturio.

Clinical Relevance

When thyroid hormones are produced at abnormal levels, symptoms can develop.

Hyperthyroidism

Hyperthyroidism is the inappropriate secretion of excessive amounts of thyroid hormones (T3 and T4), leading to an abnormal increase in the basal metabolic rate. 

  • Etiology:
    • Graves’ disease (autoimmune disease caused by TSH-receptor antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins)
    • Multinodular goiter Goiter A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Goiter
    • Toxic thyroid adenoma
    • TSH-secreting pituitary adenomas Pituitary adenomas Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas
  • Clinical presentation: 
    • Unintentional weight loss
    • Feeling hot
    • Tachycardia/palpitations
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Anxiety/irritability and insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Pretibial myxedema
    • Lid lag of the eyelids during vertical eye movements
  • Diagnosis: by laboratory assessment
    • Primary hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism: ↓ TSH + ↑ free T4
    • Secondary hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism due to TSH-secreting adenoma: ↑ TSH + ↑ free T4
  • Management: 
    • Medications
    • Surgery
    • Radioactive iodine

Hypothyroidism

Hypothyroidism is the inadequate secretion of thyroid hormone, leading to an abnormal decrease in the metabolic rate. 

  • Etiology:
    • Hashimoto’s thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). Thyroiditis
    • Iodine deficiency
    • Thyroid infiltration
    • Congenital agenesis/dysgenesis
  • Clinical presentation: 
    • Difficulty losing weight
    • Feeling cold
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Fatigue
    • Hyporeflexia
  • Diagnosis: by laboratory assessment
    • Primary hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: ↑ TSH + ↓ free T4
    • Secondary hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism (adenomas, hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism): ↓ TSH + ↓ free T4
  • Management: 
    • Levothyroxine (LT4) supplementation
    • Treat any underlying conditions.

References

  1. Brent, G.A. (2020). Thyroid hormone action. UpToDate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/thyroid-hormone-action 
  2. Ross, D.S. (2020). Overview of the clinical manifestations of hyperthyroidism in adults. UpToDate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/overview-of-the-clinical-manifestations-of-hyperthyroidism-in-adults 
  3. Saladin, K.S., Miller, L. (2004). Anatomy and physiology, 3rd ed., pp. 647–648. 

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