Question 17

College Answer

Thyroid hormones consist of thyroxine (T4), tri-iodothyronine (T3) and reverse T3 (rT3). It was expected candidates would briefly describe each of these. T4 is a pro-hormone synthesized from tyrosine in follicular cells of the thyroid gland and represents 80% of body’s thyroid hormone production. It exists in free form, plasma protein bound (albumin and pre-albumin (TBPA) and tissue protein bound thyroid-binding globulin (TBG) and has a half-life around 7 days. Tri-iodothyronine (T3) is the most biologically active thyroid hormone (5 times T4), is produced directly from tyrosine (20%) or in the periphery by conversion of T4 (80%) with a half-life 1.5 days. Reverse T3 (rT3) is formed via peripheral conversion of T4 by de-iodination. A classic negative feedback loop exists to control thyroid hormone secretion. Thyroid Stimulating Hormone (TSH) from the anterior pituitary is controlled by Thyrotropin Releasing Hormone (TRH) from the Hypothalamus via hypothalamic-hypophyseal portal system. Both of these factors are inhibited by elevated levels of T4 and T3.
The mechanism of action is by binding to nuclear receptors to effect protein synthesis. Thyroid hormone has a wide variety of physiological effects across many systems including respiratory, cardiovascular, metabolic and growth and sexual function. 
The answer required candidates to detail both the synthesis and control of thyroid hormones  as well discussing the action of thyroid hormones. Few candidates could differentiate the roles and actions of T3 and T4. 

Discussion

• Circulation of thyroid hormones
  • Released thyroid hormones consist of 80% T4 and 20% T3
  • Circulating T4 and T3 are highly protein bound to thyroid hormone-binding globulin, a chaperone protein in the plasma 
  • T4 has a longer half life (6-7 days), gradually converted to T3 by peripheral deiodinase enzymes (ubiquitous, but mainly in the liver and kidneys)
  • T3 has a shorter half life (hours) and is the main biologically active thyroid hormone
• Actions of thyroid hormones
  • Bind to mainly nuclear receptors, which act as transcription factors, modifying protein synthesis (though there are also cytosolic and membrane receptors)
  • Most physiologically important actions are mediated by gene transcription and therefore take more than 24hrs to manifest
  • Actions of thyroid hormones include:
    • Increased cardiac output due to increased contractility, and decreased peripheral vascular resistance)
    • Increased sympathetic nervous system activity, increased sensitivity to catecholamines
    • Psychological and neurodevelopmental effects
    • Increased renal blood flow and increased clearance rate of renally cleared substances
    • Increased hepatic protein synthesis and increased hepatic blood flow, with increased clearance rate of substances metabolised by the liver
    • Increased gastrointestinal motility and increased appetite
    • Increased blood flow to skeletal muscle
    • Increased shivering and nonshivering thermogenesis
    • Increased total body metabolic rate and oxygen consumption:
      • Increased gluconeogenesis increased hepatic glucose output
      • Decreased efficiency of mitochondrial electron transport, resulting in heat production
      • Increased lipolysis in white adipose tissue, ncreased free fatty acid release, increased hepatic lipogenesis, and increased use of lipids as metabolic fuel substrate
      • Reverse cholesterol transport
• Regulation of thyroid hormones
  • Release of TRH is stimulated by low T4/T3 levels and cold temperature
  • TRH stimulates TSH release (which is inhibited by high T4/T3 levels, as well as somatostatin, dopamine and cortisol)
  • TSH stimulates T3 and T4 release
  • Conversion of T4 into T3 is also controlled by regulation of peripheral deiodinase activity

Stathatos, Nikolaos. "Thyroid physiology." Medical Clinics 96.2 (2012): 165-173.

Stathatos, Nikolaos. "Anatomy and physiology of the thyroid gland." The thyroid and its diseases. Springer, Cham, 2019. 3-12.

Maenhaut, C., et al. "Ontogeny, anatomy, metabolism and physiology of the thyroid." Endotext [Internet] (2015).