Hormone Action

Thyroid Hormone

The hypothalamus secretes thyroptophin-releasing hormone (TRH), which stimulates the production of thyroid-stimulating hormone (TSH) from the anterior pituitary gland. In turn, TSH stimulates thyroid hormone synthesis and secretion from the thyroid gland. High serum concentrations of thyroid hormones inhibit TRH and TSH secretion in a classical negative feedback loop. The two principle thyroid hormones, thyroxine (T4) and triiodotyronine (T3), are vital for cell metabolism, normal growth and development. Thyroid hormones also exert significant effects on the cardiovascular system, reproductive system, and central nervous system.

Thyroid hormones enter cells via diffusion through cell membranes and bind to specific receptors within the nucleus. Gene transcription is activated when the hormone-receptor complex interacts with the DNA of responsive genes. The many physiologic processes affected by thyroid hormones occur via thyroid hormone receptors. These receptors are members of a large super-family of nuclear receptors that modulate gene expression by functioning as hormonally-activated transcription factors. Thyroid hormone receptors encapsulate three functional domains: a ligand-binding domain, a DNA-binding domain, and a transactivation domain that forms complexes with other transcription factors to either activate or repress transcription. The four currently recognized mammalian thyroid hormone receptors are alpha-1, alpha-2, beta-1, and beta-2, and patterns of expression among these different forms vary by tissue and by developmental stage.

Thyroid hormones have profound effects on lipid and carbohydrate metabolism. Thyroid hormones increase basal metabolic rate by stimulating the metabolic activities within most tissues. Increased body heat production is one consequence of this activity. The levels of thyroid hormone are inversely correlated with triglyceride and cholesterol concentrations in plasma. In particular, fat mobilization is stimulated by increased levels of thyroid hormone which leads to increased plasma concentrations of fatty acids. In many tissues, thyroid hormones also promote the oxidation of fatty acids. With respect to carbohydrate metabolism, thyroid hormones increase the biosynthesis of new glucose and stimulate glucose entry into cells.

In addition to regulating metabolism, thyroid hormones also have direct effects on muscle growth and bone development. Thyroid hormones sustain normal muscle growth by controlling the rates of protein synthesis and degradation. Excessive thyroid hormone secretion diminishes protein synthesis and increases protein degradation, resulting in a catabolic state. The growth-promoting effect of thyroid hormone in bone and developing cartilage is coupled with that of growth hormone, a clear indication that multiple endocrine controls are involved.

Although the mechanisms by which thyroid hormone mediates fetal and neonatal brain development are not well understood, it is well accepted that thyroid hormone is essential to normal brain development. Significant changes in mammalian thyroid function take place during pregnancy. The rise in estrogen levels induces a dramatic increase in the transport protein T4-binding globulin (TBG). Elevated TBG synthesis leads to lower T4 concentrations, which elevates TSH secretion by the pituitary gland. The net effect is an increased demand on the thyroid gland and thus enhanced production and secretion of T3 and T4. Recent studies have demonstrated that any impairment in maternal thyroid function during fetal development can potentially interfere with normal fetal development. Several environmental contaminants have been shown in animal studies to displace thyroxine from serum carrier proteins and increase thyroid hormone metabolism resulting in a hypothyroid state. Therefore, there is concern that exposure to environmental contaminants could also affect human thyroid function although at present there are no epidemiological studies that provide overwhelming evidence of such an occurrence in the human population.