Thyroid – anatomy & function

Thyroid Hormone Regulation and Metabolism

1. TRH and TSH Secretion:
   • Thyrotropin-Releasing Hormone (TRH): Increases the secretion of Thyroid-Stimulating Hormone (TSH).
   • TSH: Stimulates the synthesis and secretion of T3 (triiodothyronine) and T4 (thyroxine) by the thyroid gland.
2. Feedback Inhibition:
   • T3 and T4: Inhibit the secretion of TSH both directly and indirectly by suppressing the release of TRH.
3. Conversion and Metabolism:
   • T4 to T3 Conversion: T4 is converted to the more active T3 in the liver and many other tissues by the action of T4 monodeiodinases.
   • Conjugation and Excretion:
     • Some T4 and T3 are conjugated with glucuronide and sulfate in the liver.
     • These conjugated forms are excreted in the bile and partially hydrolyzed in the intestine.
     • Some T4 and T3 formed in the intestine may be reabsorbed.
4. Drug Interactions:
   • Potential Sites of Interaction: Drug interactions can occur at various points in this regulatory and metabolic pathway.

Active and Inactive Forms of Thyroid Hormones

1. Triiodothyronine (T3):
   • Active Form: T3 is the most biologically active thyroid hormone. It is responsible for most of the physiological effects of thyroid hormones, including regulation of metabolism, heart rate, and growth and development.
   • Mechanism: T3 binds to thyroid hormone receptors in the nucleus of cells, leading to modulation of gene expression and subsequent physiological effects.
   • Action
     • Metabolic Regulation: Increases basal metabolic rate and influences various metabolic processes.
     • Cardiovascular Effects: Increases heart rate, cardiac output, and promotes vasodilation.
     • Developmental Role: Crucial for normal growth and development, particularly in the central nervous system
2. Thyroxine (T4):
   • Prohormone: T4 is less active than T3. It serves primarily as a precursor to T3.
   • Conversion: T4 is converted to T3 in peripheral tissues by deiodinases (mainly in the liver and kidneys). This conversion is crucial for maintaining adequate levels of active T3.
   • Action
     • Precursor Role: Acts as a reservoir for T3, ensuring a stable supply of the active hormone.
     • Clinical Measurement: Often measured in clinical settings to assess thyroid function because it is more stable and has a longer half-life than T3.
3. Reverse Triiodothyronine (rT3):
   • Inactive Form: rT3 is an inactive form of thyroid hormone. It is produced from T4 through the action of deiodinases, particularly during periods of illness, fasting, or stress.
   • Significance: Elevated levels of rT3 can indicate a state of “non-thyroidal illness syndrome” or “euthyroid sick syndrome,” where despite normal thyroid gland function, peripheral metabolism of thyroid hormones is altered, often in response to acute or chronic illness.

Function: 

• The thyroid hormones increase the metabolic activities of almost all the tissues of the body. 
• The rate of utilisation of food for energy is increased. 
• The growth rate of young people is greatly accelerates, and mental processes are excited. 

Effects on Foetal Development

• After 11 weeks of gestation, the foetus is dependent on its own thyroid hormone
• Although some foetal growth occurs in the absence of foetal thyroid hormone, brain development and skeletal maturation are impaired → cretinism (mental retardation and dwarfism)

Effects on Oxygen Consumption, Heat Production and Free Radical Formation

• T3 increases oxygen consumption and heat production in part by stimulation of the sodium-potassium-pump in al tissues such as the brain, spleen and testis. 
• Increase size and number of mitochondria (? cause of result of increased activity?)
• Decreased superoxide dismutase levels → increased free radial formation 

Cardiovascular Effects

• T3 stimulates transcription of myosin heavy chain α  and inhibits myosin heavy chain β → improves contractility
• T3 also increased the diastolic tone of the heart
• Positive inotropic and chronotropic effects on the heart

Sympathetic Effects

• Increased numbers of beta-adrenergic receptors in heart muscle, skeletal muscles, adipose tissues and lymphocytes
• Increase sensitivity to catecholamines 

Pulmonary Effects

• Maintain normal hypoxic and hypercapnic drive in the respiratory centre

Haematopoeitic Effects

• High levels of thyroid hormone → increased cellular demand for oxygen → increased erythropoietin 
• Increased 2,3-DPG → increased oxygen dissociation from the haemoglobin and increases oxygen availability to tissues

Gastrointestinal Effects

• Stimulate gut motility

Skeletal Effects

• Stimulate bone turnover, increasing bone resorption and to a lesser extent, bone formation

Neuromuscular Effects

• Increased protein turnover and loss of muscle tissue (myopathy)
• Increase speed of muscle contraction and relaxation → fast reflexes

Effects on Lipid and Carbohydrate Metabolism

• Increases hepatic gluconeogenesis and glycogenolysis as well as intestinal glucose absorption (high thyroid hormone levels exacerbates DM)
• Increased cholesterol synthesis and degradation
• Increased lipolysis 

Endocrine Effects

• Increase metabolic turnover of many hormones and drugs
• Influence ovulation (hypo&hyperthyroidism → infertility)

Other functions of the thyroid:

• The thyroid also produces calcitonin
  • a peptide hormone that functions to inhibit the osteoclast mediated bone resporption. Calcitonin is secreted by C cells (neuroendocrine cells). The secretion of calcitonin is under the control of serum [Ca]. 
  • When administered IV, calcitonin produces a rapid and dramatic decline in levels calcium and phosphorus.  
  • The major effect of the hormone is to inhibit osteoclastic bone resorption.  
  • Calcitonin also acts on the kidneys to inhibit the reabsorption of phosphate. 
  • Although calcitonin is also to counter PTH in the control of calcium homeostasis, it is unlikely that calcitonin plays an essential physiologic role in humans.  
  • Calcitonin is important as a tumour marker in medullary thyroid carcinoma and also has therapeutic uses as an inhibitor of osteoclastic  bone resorption e.g. in Paget’s disease.