Thyroid hormones

Thyroid hormones are vital chemical messengers that regulate how the body uses energy. Produced by the thyroid gland, these hormones are primarily responsible for managing metabolism. Metabolism is the process by which cells use energetic compounds to function. The two main hormones are triiodothyronine, known as T3, and thyroxine, known as T4.

These hormones are tyrosine-based and contain iodine, which humans must get from their food. Because they influence energy expenditure and cell development, they are essential for nearly every cell in the human body.

The production of these hormones is a complex, step-by-step biological process. It begins in the thyroid follicular cells with a large protein called thyroglobulin.

First, a mechanism called iodide trapping occurs. A protein called the Na+/I− symporter pumps iodide ions into the cell. This process uses a sodium concentration gradient to move iodide against its own gradient. Once inside, the iodide moves into the follicle lumen via a transporter called pendrin. In this lumen, an enzyme called thyroid peroxidase (TPO) helps turn the iodide into reactive iodine.

Once the iodine is reactive, it attaches to specific parts of the thyroglobulin protein. These parts are called tyrosyl residues. There are approximately 100 to 120 of these residues on each thyroglobulin molecule. The TPO enzyme facilitates a process where these iodinated residues pair up. When two specific residues pair, they form T4, which contains four iodine atoms.

If the pairing involves a different configuration, it forms T3, which has three iodine atoms.

Finally, the cell pulls the iodinated thyroglobulin back inside through endocytosis. Enzymes called proteases then cleave the protein to release the active T3 and T4 into the blood. This release is believed to happen largely through monocarboxylate transporters, specifically MCT 8 and 10.

These hormones serve different roles once they enter the bloodstream. T4 is the major form of thyroid hormone found in the blood. It has a relatively long half-life of about one week. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. However, T4 is not the most active form. To become fully functional, T4 must be converted into T3 within the target cells. This conversion is performed by selenium-containing enzymes called deiodinases. Because these enzymes require selenium, dietary selenium is essential for producing active T3. T3 is three to four times more potent than T4.

Scientists have made significant discoveries regarding these molecules over the last century. In 1915, the American chemist Edward Calvin Kendall successfully isolated thyroxine. Later, in 1926, Charles Robert Harington and George Barger produced synthetic thyroxine. These breakthroughs allowed medicine to address hormone deficiencies. Today, if a person has hypothyroidism, meaning a hormone deficiency, they can take replacement medication. Levothyroxine is a manufactured version of T4. It is metabolized slowly, so patients usually only need to take it once a day. In 2020, levothyroxine was the second most commonly prescribed medication in the United States, with over 98 million prescriptions. It is even included on the World Health Organization's List of Essential Medicines.

The importance of these hormones is seen in how they affect many bodily systems. They increase the basal metabolic rate and affect how the body synthesizes proteins. They also help regulate the growth of long bones and the maturation of the nervous system. Furthermore, they increase the body's sensitivity to catecholamines, such as epinephrine, which is especially important during cold exposure. Thyroid hormones even play a role in heat generation. Interestingly, the body also produces thyronamines, such as T1a and T0a. These are processed from T3 through decarboxylation and deiodination. While their exact mechanisms are unknown, they may inhibit neuronal activity, which is important for the hibernation cycles of mammals.

Maintaining the correct balance of iodine and thyroid function is critical for health. If a person lacks enough iodine, the thyroid cannot produce enough T3 and T4. This deficiency can cause the thyroid tissue to enlarge, creating a condition called a simple goitre. Proper hormone levels are also vital during pregnancy. If a pregnant woman has an untreated low-functioning thyroid, her fetus faces a higher risk of congenital disabilities. Because of this, doctors often must increase hormone dosages during pregnancy. While these hormones are generally well tolerated, they must be managed carefully in older patients to avoid risks to the heart. Understanding these tiny molecules helps us understand the very engine of human life.