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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.

Another controversy continues to rage between the Food & Drug Administration and a group that includes Synthroid maker Abbott Laboratories as well as several endocrinology associations. Although FDA believes that generic levothyroxine is equivalent to the brand-name drug, the group disagrees, claiming that differences in the way tablets are compounded makes for different absorption rates that could affect treatment outcomes. "It turns out the difference between certain generics and brands is considerably greater than 12.5%," claims Carlos R. Hamilton Jr., president of the American Association of Clinical Endocrinologists. "Does this make any difference? A lot of endocrinologists think it does."

The T4 story is far from complete. Researchers continue to explore issues such as the nature of deiodinase enzymes, tumors that contain deiodinases, and how T4 replacement should be handled during pregnancy.—ELIZABETH WILSON


Is One Thyroxine As Good As Another?

If Gertrude Stein had worried about her thyroid, she might have said “thyroxine is thyroxine is thyroxine is thyroxine.” But the drug, used to treat thyroid deficiency, is the second most prescribed in the U.S., doing hundreds of millions of dollars in business for its manufacturers. And when the U.S. Food & Drug Administration last year began allowing sodium levothyroxine, (the form of thyroxine most easily absorbed) in generic form to be interchangeable with brand-name versions, drug companies and many endocrinologists began waging a campaign to convince FDA that not all thyroxine (T4 ) is created equal.

Although it seems the issue should be cut and dry, determining whether or not different brands of T4 are therapeutically indistinct from each other is anything but. It’s true that the only thing chemically different about the pills is their inert ingredients, such as binders. But some drug companies and doctors say studies show that a combination of factors—including the inert ingredients, how T4 is treated and produced in the manufacturing process, as well as how long it’s been on the shelf—affect how fast and how much of the drug is absorbed. And that, they say, can create trouble for patients whose brand of T4 can now be switched by a pharmacist without their knowledge.

FDA maintains that numerous bioequivalence studies have shown that a number of T4 brands, manufactured under strict new standards, are essentially interchangeable. “FDA believes that whatever differences exist in rate and extent of absorption from different products are not clinically meaningful as long as the products have similar potency,” says David G. Orloff, director of FDA’s Division of Metabolic & Endocrine Drug Products.

In fact, Orloff says, even studies on the same drugs show absorption differences. “Those differences are related to the fact that bioavailability studies are conducted in people, as opposed to test tubes,” he says. “There’s some inherent variability that can’t be accounted for.”

Last month, FDA, members of several endocrinological and thyroid societies, and representatives from companies such as Abbott and Sandoz, held a workshop in Washington, D.C. “Both sides presented their views, and nobody changed their minds,” says Carlos R. Hamilton Jr., president of the American Association of Clinical Endocrinologists (AACE). “That didn’t come as a great surprise.”

What makes generic T4 distinct from other generic versions of big-name drugs? For one thing, according to John Leonard, vice president of medical and scientific affairs at Abbott, T 4 is an endogenous substance, like insulin and steroids, which is made by the body to control its normal function. The standard method of testing for bioequivalence—by observing blood concentrations of drugs in healthy volunteers—may be appropriate for exogenous drug like Prozac and Valium, but may not be so in the case of hormones that the body tightly regulates.

A related issue is that T 4 is one of a very few drugs with a so-called narrow therapeutic index. Doctors must work carefully with the patient to titrate an appropriate dose of these drugs, which include the blood thinner Coumadin (and its generic warfarin), as the differences between an ineffective, effective, or toxic dose is very small.

The dangers of an over- or underdose are hyperthyroidism, which can cause atrial fibrillation that can lead to stroke, or hypothyroidism, which could affect the mental development of a fetus in a pregnant woman. But, Hamilton says, most likely it interferes with attempts to stabilize the patient. “It could be life-threatening, but it’s usually not,” he says. “But it is inconvenient and aggravating—everything’s out of whack.”

Hamilton says the issue could be resolved by keeping patients on the same brand and requiring pharmacists to notify patients if a brand is switched.

T4 manufacturers such as Abbott, King Pharmaceutical’s subsidiary Jones Pharma (which makes Levoxyl) and Stevens (which makes Unithroid) insist that they, too, only have patients’ stability in mind. That altruistic stance, however, is tempered by the fact that generics being introduced by companies such as Mylan and Sandoz are poised to grab a formidable market share of a blockbuster drug. Abbott, whose Synthroid accounts for over 65% of T 4 sales, has particular reason to be concerned.

Thyroxine’s tortured regulatory history also adds to the context. In the 1980s, Flint Pharmaceuticals, Synthroid’s original manufacturer, commissioned a group at the University of California, San Francisco, led by pharmacologist Betty Dong, to compare Synthroid with other brands. When Dong’s research showed that four different brands of T4 were essentially bioequivalent, the company (which had since then been bought by Boots Pharmaceuticals) allegedly suppressed the study’s publication for seven years. The work was finally printed in the Journal of the American Medical Association in 1997, accompanied by a scathing editorial about academic freedom by a former JAMA editor, Drummond Rennie.

Because T4 had been available for decades, FDA in 1962 originally exempted the drug’s manufacturers from demonstrating its safety and efficacy. But evidence began piling up that there were serious inconsistencies from batch to batch in concentration, quality, and stability. FDA then changed its mind and required companies to submit New Drug Applications for T4 . Abbott filed an NDA in 2001, and in 2002, it received FDA approval for Synthroid. The result, FDA says, is a more consistent product.

“Products are light-years better than what they used to be in quality and potency,” Orloff says. “We believe endocrinologists have much better tools than they ever did for treating patients with thyroid hormone deficiency.”

And though the FDA is willing to keep talking, the agency considers the issue largely closed. “We have agreed to continue to engage in discussions to try to resolve the misunderstanding, but at this point, FDA has no question about its own standards,” Orloff says.

The lines are still clearly drawn, though. AACE recently conducted a survey of its members, in which over 90% of the more than 900 respondents said they supported more stringent bioequivalence standards for T4 products, as well as a limitation of pharmacists’ ability to substitute T4 brands.

Though AACE and other professional associations receive funding from drug companies like Abbott, Hamilton says preference for a particular brand isn’t the societies’ concern. “There’s no question that Abbott would love it if everybody took Synthroid. And King Pharmaceuticals would love everybody to take Levoxyl,” he says. “But we don’t take sides. We just want people to stay on what they’re already taking.”—ELIZABETH WILSON


The Top Pharmaceuticals
That Changed The World
Vol. 83, Issue 25 (6/20/05)
Table Of Contents


Thyroxine structure


  • O-(4-Hydroxy-3,5-diiodophenyl)

CAS Registry

  • 51-48-9

Other Names

  • Levothyroxine
  • T4

First marketed

1955, Flint Laboratories


  • $637 million in 2004 U.S. sales of Synthroid (the sodium salt)