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It's hard to understate the importance of the role thyroxine plays in biology. Derived from the amino acid tyrosine, and bedecked with four iodines, thyroxine is the ultimate metabolism regulator. Its reactions and products influence carbohydrate metabolism, protein synthesis and breakdown, and cardiovascular, renal, and brain function.

Without it, an animal's functions--and, in the young, development--come to a grinding halt. Tadpoles won't develop into frogs. Untreated human babies are doomed to cretinism, a condition marked by severe mental and physical retardation. Adult humans with low thyroxine levels--or hypothyroidism--suffer mental slowness, weight gain, depression, and fatigue.

Thyroxine, or tetraiodothyronine, is produced by the thyroid--in humans, it's a butterfly-shaped gland in the front of the neck. There's a lot that can interfere with a thyroid's normal generation of thyroxine (also known as T4), the most well-known being iodine deficiency. Without adequate supply of this crucial element, the thyroid can't synthesize thyroxine. The gland enlarges as it tries to take up more iodine, leading to goiter. This condition can be prevented with iodine supplements, and many industrialized countries now iodize salt.

But other thyroid problems aren't related to iodine deficiency. For example, Hashimoto's disease is an autoimmune disorder that causes the thyroid to underproduce thyroxine. And people who have had their thyroids surgically removed, or destroyed with radioactive iodine--as treatments for thyroid cancer or the hyperthyroid autoimmune disorder known as Grave's disease--don't produce any T4 at all.

Fortunately, these conditions can be alleviated for the most part by simply swallowing a replacement dose of thyroxine, a lifesaver for the large number of people with thyroid disorders. Today, more than 10 million people in the U.S. take thyroxine. Synthroid, manufactured by Abbott Laboratories and the most popular brand of thyroxine, is the second-most prescribed drug in the U.S.

For many years, desiccated animal thyroid was the source of T4 used by doctors and was touted as a near-perfect medical therapy. But, as researchers have discovered, the complete biochemical picture of the thyroid's most important ingredient, thyroxine, is far more complex. Even today, the medical community debates the role of thyroxine and the best way to use it.

EARLY WORK Kendall isolated thyroxine in 1914.COLUMBIA UNIVERSITY ARCHIVES

EARLY WORK Kendall isolated thyroxine in 1914.

Doctors and researchers recognized the thyroid's role in metabolism as far back as the late 1800s. Then, preeminent surgeon Theodor Kocher, who won a Nobel Prize in Physiology or Medicine in 1909 for his perfection of surgical thyroidectomy techniques, noted that many of his patients after surgery eventually developed the classic symptoms of hypothyroidism.

Soon, doctors found that injecting these patients with thyroid extracts from sheep reversed the symptoms. Even better, they found that patients could take the extracts orally to the same effect.

In the early 1900s, biochemist Edward C. Kendall isolated thyroxine from thyroid extract. (He also shared a Nobel Prize in Physiology or Medicine, in 1950, for his discovery of the activity of cortisone.) T4 was eventually synthesized by biochemist Charles R. Harington in 1926.


Abbott dominates the T4 market, but generics are moving in

Major levothyroxine brands as of May 2004:

Company Drug Market Share
Abbott Labs Synthroid 62%
Jones Pharmaceuticals Levoxyl 28
Forest Pharmaceuticals Levothroid 6
Stevens Unithroid 2
Vintage Levolet 1
Mylan Generic Unithroid 1
Alara Levo-T 0

New approvals for generics since June 2004:

Company Equivalent brand-name drug Approved
Alara (Sandoz) Synthroid and Levoxyl June 2004
Mylan Levoxyl June 2004
Lannett Levoxyl June 2004
Mylan Synthroid July 2004
Lannett Synthroid December 2004

SOURCES: IMS Health, Sandoz

THE THYROID is the only part of the body that uses iodine. Thyroxine is formed there by thyroperoxidase enzymes, which affix iodine atoms to the rings of tyrosine residues of the protein thyroglobulin. While most of the T4 remains bound to thyroglobulin, small amounts break free with the help of proteases and circulate throughout the body to act on its metabolism.

In the 1950s, researchers discovered another major thyroid hormone, triiodothyronine, or T3. This far more potent hormone is largely synthesized from T4 by deiodinase enzymes outside the thyroid. The body is therefore able to use a dose of T4 to produce its own T3. In the 1960s, researchers also discovered that sodium levothyroxine is better absorbed than the free acid form of thyroxine. Doctors increasingly began prescribing synthetic sodium levothyroxine, and that compound is now the predominant form of thyroid hormone replacement therapy.

But in recent years, the biology of thyroxine has taken on added complexity. Dogged by persistent complaints of lack of well-being and energy from a consistent percentage of people taking T4, some researchers began to revisit the idea of combination therapy, hypothesizing that both T3 and T4 might be better, physiologically. Many people claimed to feel better as well, and a 1999 study appeared to back that up. Several subsequent attempts to replicate those results failed, however. "Most of the studies have not panned out," says Jeffrey R. Garber, chief of endocrinology at Harvard Vanguard Medical Associates