Control of Thyroid Hormone Synthesis and Secretion

The chief stimulator of thyroid hormone synthesis is thyroid-stimulating hormone from the anterior pituitary. Binding of TSH to receptors on thyroid epithelial cells seems to enhance all of the processes necessary for synthesis of thyroid hormones, including synthesis of the iodide transporter, thyroid peroxidase and thyroglobulin.

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 and release diminish.

The thyroid gland is part of the hypothalamic-pituitary-thyroid axis, and control of thyroid hormone secretion is exerted by classical negative feedback, as depicted in the diagram. 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, leading to "shutdown" of thyroid epithelial cells. Later, when blood levels of thyroid hormone have decayed, the negative feedback signal fades, and the system wakes up again.

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. This makes sense considering the known ability of thyroid hormones to spark body heat production.

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 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.

Control of Thyroid Hormone Synthesis and Secretion

Each of the processes described above appears to be stimulated by thyroid-stimulating hormone from the anterior pituitary gland. Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin.

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 and release diminish.

Synthesis and Secretion of Thyroid Hormones

The entire synthetic process occurs in three major steps, which are, at least in some ways, analagous to those used in the manufacture of integrated circuits (ICs):

•Production and accumulation of the raw materials (in the case of ICs, a large wafer of doped silicon)
•Fabrication or synthesis of the hormones on a backbone or scaffold of precursor (etching several ICs on the silicon wafer)
•Release of the free hormones from the scaffold and secretion into blood (cutting individual ICs out of the larger wafer and distributing them)
The recipe for making thyroid hormones calls for two principle raw materials:

•Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle - colloid is essentially a pool of thyroglobulin. A molecule of thyroglobulin contains 134 tyrosines, although only a handful of these are actually used to synthesize T4 and T3.
•Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid epithelial cells, which have on their outer plasma membrane a sodium-iodide symporter or "iodine trap". Once inside the cell, iodide is transported into the lumen of the follicle along with thyroglobulin.
Fabrication of thyroid hormones is conducted by the enzyme thyroid peroxidase, an integral membrane protein present in the apical (colloid-facing) plasma membrane of thyroid epithelial cells. Thyroid peroxidase catalyzes two sequential reactions:

1. Iodination of tyrosines on thyroglobulin
 
2. Synthesis of thyroxine or triiodothyronine from two iodotyrosines.

Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free hormone into blood.

Thyroid hormones are excised from their thyroglobulin scaffold by digestion in lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis proceeds in the following steps:

•Thyroid epithelial cells ingest colloid by endocytosis from their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone.
 
•Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones.
 
•Finally, free thyroid hormones apparently diffuse out of lysosomes, through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.

Chemistry of Thyroid Hormones

Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to iodine. The two principal thyroid hormones are:
 
thyroxine (also known as T4 or L-3,5,3',5'-tetraiodothyronine)

triiodothyronine (T3 or L-3,5,3'-triiodothyronine)
 
The thyroid hormones are basically two tyrosines linked together with the critical addition of iodine at three or four positions on the aromatic rings. The number and position of the iodines is important. Several other iodinated molecules are generated that have little or no biological activity; so called "reverse T3" (3,3',5'-T3) is such an example.

Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4 circulating in blood is bound to carrier proteins. The principle carrier of thyroid hormones is thyroxine-binding globulin, a glycoprotein synthesized in the liver. Two other carriers of import are transthyrein and albumin. Carrier proteins allow maintenance of a stable pool of thyroid hormones from which the active, free hormones are released for uptake by target cells.

Anatomy of the Thyroid and Parathyroid Glands

Thyroid glands are located in the neck, in close approximation to the first part of the trachea. In humans, the thyroid gland has a "butterfly" shape, with two lateral lobes that are connected by a narrow section called the isthmus. Most animals, however, have two separate glands on either side of the trachea. Thyroid glands are brownish-red in color.

Close examination of a thyroid gland will reveal one or more small, light-colored nodules on or protruding from its surface - these are parathyroid glands (meaning "beside the thyroid").

The microscopic structure of the thyroid is quite distinctive. Thyroid epithelial cells - the cells responsible for synthesis of thyroid hormones - are arranged in spheres called thyroid follicles. Follicles are filled with colloid, a proteinaceous depot of thyroid hormone precursor.

In addition to thyroid epithelial cells, the thyroid gland houses one other important endocrine cell. Nestled in spaces between thyroid follicles are parafollicular or C cells, which secrete the hormone calcitonin.

The structure of a parathyroid gland is distinctly different from a thyroid gland. The cells that synthesize and secrete parathyroid hormone are arranged in rather dense cords or nests around abundant capillaries.