Mechanism of Action and Physiologic Effects of Thyroid Hormones

Thyroid Hormone Receptors and Mechanism of Action

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones.

Thyroid hormones enter cells through membrane transporter proteins. A number of plasma membrane transporters have been identified, some of which require ATP hydrolysis; the relative importance of different carrier systems is not yet clear and may differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes.

For the purpose of illustration, consider one mechanism by which thyroid hormones increase the strength of contraction of the heart. Cardiac contractility depends, in part, on the relative ratio of different types of myosin proteins in cardiac muscle. Transcription of some myosin genes is stimulated by thyroid hormones, while transcription of others in inhibited. The net effect is to alter the ratio toward increased contractility.

For additional details on mechanism of action and how these receptors interact with other transcription factors, examine the section Thyroid Hormone Receptors.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones. While not strictly necessary for life, thyroid hormones have profound effects on many "big time" physiologic processes, such as development, growth and metabolism, and deficiency in thyroid hormones is not compatible with normal health. Additionally, many of the effects of thyroid hormone have been delineated by study of deficiency and excess states, as discussed briefly below.

Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smouldering fire. 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. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels - one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
• 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, as evidenced by 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 indiction that complex physiologic processes like growth depend upon multiple endocrine controls.

Development: A classical experiment in endocrinology was the demonstration that tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal 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.

Thyroid Disease States

Disease is associated with both inadequate production and overproduction of thyroid hormones. Both types of disease are relatively common afflictions of man and animals.

Hypothyroidism is the result from any condition that results in thyroid hormone deficiency. Two well-known examples include:

• Iodine deficiency: Iodide is absolutely necessary for production of thyroid hormones; without adequate iodine intake, thyroid hormones cannot be synthesized. Historically, this problem was seen particularly in areas with iodine-deficient soils, and frank iodine deficiency has been virtually eliminated by iodine supplementation of salt.
• Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the gland are clearly an important cause of hypothyroidism.

Common symptoms of hypothyroidism arising after early childhood include lethargy, fatigue, cold-intolerance, weakness, hair loss and reproductive failure. If these signs are severe, the clinical condition is called myxedema. In the case of iodide deficiency, the thyroid becomes inordinantly large and is called a goiter.

The most severe and devestating form of hypothyroidism is seen in young children with congenital thyroid deficiency. If that condition is not corrected by supplemental therapy soon after birth, the child will suffer from cretinism, a form of irreversible growth and mental retardation.

Most cases of hypothyroidism are readily treated by oral administration of synthetic thyroid hormone. In times past, consumption of dessicated animal thyroid gland was used for the same purpose.

Hyperthyroidism results from secretion of thyroid hormones. In most species, this condition is less common than hypothyroidism. In humans the most common form of hyperthyroidism is Graves disease, an immune disease in which autoantibodies bind to and activate the thyroid-stimulating hormone receptor, leading to continual stimulation of thyroid hormone synthesis. Another interesting, but rare cause of hyperthyroidism is so-called hamburger thyrotoxicosis.

Common signs of hyperthyroidism are basically the opposite of those seen in hypothyroidism, and include nervousness, insomnia, high heart rate, eye disease and anxiety. Graves disease is commonly treated with anti-thyroid drugs (e.g. propylthiourea, methimazole), which suppress synthesis of thyroid hormones primarily by interfering with iodination of thyroglobulin by thyroid peroxidase.

Advanced and Supplemental Topics

• Thyroid Hormone Receptors
• Thyroid Hormones: Pregnancy and Fetal Development
• Hamburger Thyrotoxicosis

Send comments to Richard.Bowen@colostate.edu

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