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. 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. T3 is far more active than T4, so most T4 is converted to T3 in the periphery (e.g., 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 and hypothyroidism.

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Overview

Hormones released by the 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 and skeletal development
  • Calcitonin: 
    • Produced by C cells in the thyroid gland
    • Works to ↓ Ca2+ serum levels, opposing the action of parathyroid hormone (PTH)
    • In bone: stimulates osteoblasts → promotes calcium deposition and ossification
    • In kidneys: stimulates phosphate reabsorption → ↑ ossification

The hypothalamic-pituitary-thyroid (HPT) axis

Release of T3 and T4 is regulated by hormones secreted by the hypothalamus and 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 to release TSH.
  • Thyroid-stimulating hormone (TSH) stimulates the 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 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 →  stimulates transcription/translation of a number of proteins including:
    • Na+/K+ pump
    • Gluconeogenic enzymes
    • Respiratory enzymes
    • Myosin heavy chains
    • β-adrenergic receptors
  • These proteins generally all:
    • ↑ Cellular metabolism
    • ↑ Cellular oxygen consumption
    • ↑ Cellular glucose
    • ↑ Circulation and respiration
    • Promote 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 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)
    • Multinodular goiter
    • Toxic thyroid adenoma
    • TSH-secreting pituitary adenomas
  • Clinical presentation: 
    • Unintentional weight loss
    • Feeling hot
    • Tachycardia/palpitations
    • Diarrhea
    • Anxiety/irritability and insomnia
    • Pretibial myxedema
    • Lid lag of the eyelids during vertical eye movements
  • Diagnosis: by laboratory assessment
    • Primary hyperthyroidism: ↓ TSH + ↑ free T4
    • Secondary 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
    • Iodine deficiency
    • Thyroid infiltration
    • Congenital agenesis/dysgenesis
  • Clinical presentation: 
    • Difficulty losing weight
    • Feeling cold
    • Constipation
    • Fatigue
    • Hyporeflexia
  • Diagnosis: by laboratory assessment
    • Primary hypothyroidism: ↑ TSH + ↓ free T4
    • Secondary hypothyroidism (adenomas, 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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