Thyroid Hormones

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

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 + DIT → T₃ 
  • 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).

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

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.