Mechanism of Hypothyroidism

The chief stimulator of thyroid hormone synthesis is thyroid-stimulating hormone from the anterior pituitary part of the brain. Binding of TSH to receptors on thyroid epithelial cells induce synthesis of the iodide transporter, thyroid peroxidase and thyroglobulin, which is used to produce the thyroid hormone.

The magnitude of the TSH signal also sets the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation. Conversely, when TSH levels are low, rates of thyroid hormone synthesis decreases.

The thyroid gland is part of the hypothalamic-pituitary-thyroid axis, and control of thyroid hormone secretion is by negative feedback. Thyroid-releasing hormone (TRH) from the hypothalamus stimulates TSH from the pituitary, which stimulates thyroid hormone release. As blood concentrations of thyroid hormones increase, they inhibit both TSH and TRH. Later, when blood levels of thyroid hormone have declined, the negative feedback signal fades, and TSH and TRH starts producing.

A number of other factors have been shown to influence thyroid hormone secretion. In rodents and young children, exposure to a cold environment triggers TRH secretion, leading to enhanced thyroid hormone release. As thyroid hormone controls metabolism, and increased body heat production.

Thyroid Hormone Receptors and Mechanism of Action

Receptors for thyroid hormones are found in the cells. Thyroid hormones enter cells through membrane transporter proteins. After entering the cell, it reaches the nucleus. The hormone will then bind to its receptor and this leads to signal transduction in the nucleus. This modulates gene expression, either by stimulating or inhibiting transcription of specific genes.

One of the function that thyroid hormones control is the strength of contraction of the heart. Cardiac contractility depends on the ratio of different types of myosin proteins in cardiac muscle. Transcription or inhibition of some myosin protein genes is controlled by the binding of thyroid hormones. This leads to alteration of the ratio toward increased contractility.

Disorders of Thyroid Hormone Receptors

People whose thyroid hormone receptors are not functioning have hypothyroidism. They will have elevated serum concentrations of T3 and thyroxine and normal or elevated serum concentrations of TSH. More than half of affected children show attention-deficit disorder, which is intriguing considering the role of thyroid hormones in brain development. In most affected families, this disorder is transmitted as a dominant trait, which suggests that the mutant receptors act in a dominant negative manner.

Mice with targeted deletions in thyroid receptor genes have provided additional understanding of the possible roles of different forms of thyroid hormone receptors.

Physiologic Effects of Thyroid Hormones

Most cells in the body has receptors for thyroid hormone, meaning that many physiological processes such as development, growth and metabolism depend on the thyroid hormone in a way or another. Deficiency in this hormone may cause adverse health effects. 

Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is increased body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. A few examples of specific metabolic effects of thyroid hormones include:

• Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids in many tissues.

• Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth: Thyroid hormones are clearly necessary for normal growth in children and young animals,evident in the growth-retardation observed in thyroid deficiency. Not surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone, a clear indication that complex physiologic processes like growth depend on thyroid hormone.

Development: An experiment in endocrinology demonstrated that tadpoles deprived of thyroid hormone fail to undergo metamorphosis. This shows that normal levels of thyroid hormone are essential to the development of the fetal brain.

Other Effects: As mentioned above, there do not seem to be organs and tissues that are not affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

• Cardiovascular system: Thyroid hormones increases heart rate, cardiac contractility and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs.
• Central nervous system: Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.
• Reproductive system: Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility

To people out there who needs help with the visualisation of this hormone function, here are 2 videos that you can watch!!