In the Mix: Combination Therapy for Hypothyroidism Gets Another Look

While evidence-based guidelines don’t encourage it, many endocrinologists recognize a need to give combination therapy a trial in some patients with hypothyroidism.

Although treatment guidelines specify levothyroxine as the standard of care for hypothyroidism, many thyroid specialists acknowledge a dirty little not-so-secret: When pressed by an insistent patient, many clinicians find it prudent to explore a trial of T4 and T3 combination therapy.

And now some experts are saying new evidence is making them take another look at combination therapy.

Decades ago, patients received extracts that contained both hormones. That stopped with the advent of a synthetic version of T4 in levothyroxine. But some 10% to 20% of patients have consistently expressed dissatisfaction with the results of this treatment, and in the internet age there is growing danger that these patients will seek out treatments than can harm them.

“The professional societies that issue guidelines have not endorsed combination therapy, but neither have they condemned it,” says Leonard Wartofsky, MD, director of the thyroid cancer research unit at the MedStar Health Research Institute in Washington, D.C., and a former president of both the Endocrine Society and the American Thyroid Association. “They have gotten a little looser in terms of recognizing data that raise significant questions that at least warrant further study.” But he notes that guideline writers base their recommendations largely on randomized clinical trials, which have not found a benefit to combination therapy over the established T4 therapy. Without new information, it’s difficult to change guideline recommendations.

“The professional societies that issue guidelines have not endorsed combination therapy, but neither have they condemned it. They have gotten a little looser in terms of recognizing data that raise significant questions that at least warrant further study.” – Leonard Wartofsky, MD, director, Thyroid Cancer Research Unit, MedStar Health Research Institute, Washington, D.C.

Antonio C. Bianco, MD, PhD, professor of medicine at the University of Chicago and also a former president of the American Thyroid Association, says that these trials could be looked at in a different way: Because the trials haven’t found a difference between the treatments, then the two treatments can be considered equivalent.

Problems Converting T4 to T3

Bianco notes that monotherapy with T4 does not restore circulating T3 levels, which provides a rationale for combination therapy. There is also evidence — not from clinical trials — that a subset of hypothyroid patients could benefit from combination treatment. A recently discovered genetic polymorphism that occurs in some 16% of the population of the United Kingdom interferes with metabolism of T4 to T3. The polymorphism has been replicated in a mouse model to generate a form of hypothyroidism that can be corrected with administration of T3.

Although this association has not been replicated in another population, the existence of a genetic cause interfering with generation of T3 from T4 provides a potential mechanism to explain why many patients are not satisfied with receiving T4 alone.

Francesco S. Celi, MD, MHSc, chair of the Division of Endocrinology, Diabetes, and Metabolism at Virginia Commonwealth University in Richmond, says that there is also animal evidence that T3 administration is required to get this active form into all tissues.

Which Patients to Treat

These kinds of evidence can be heartening to endocrinologists who must decide how to deal with patients who come to appointments armed with internet research that has convinced them that T3 will cure their ills.

Wartofsky will consider such a request when a patient on T4 replacement therapy complains about symptoms such as “feeling lousy,” “brain fog,” and weight gain without increased food consumption.

He starts by measuring the patient’s free T4 and T3 ratio. If the T3 levels are ample, he suggests that the test results indicate thyroid hormones are not the problem and the patient may be suffering from depression. But if the free T3 is low relative to the free T4, he’ll suggest a trial of adding T3 for three to six months to see if it alleviates the patient’s symptoms.

Celi is also amenable to a trial of combination therapy if the patient is adamant or he feels they have exhausted other treatment options. “I make a sort of contract with my patients, asking them what symptoms that they attribute to hypothyroidism bother them the most,” Celi tells Endocrine News. “Then after three to six months of combination therapy, we revisit the symptoms and make an assessment as to whether we made a difference or not. If there is a positive difference, we continue with the combination therapy. Otherwise, it is really not worth the cost and effort of taking extra medication.”

He makes a very rough estimate that even among those who embark on a trial of T3, only about a third report enough benefit to continue taking T3. The lack of a timed-release formulation — and the need to take a pill more frequently than once a day — remains a hurdle in taking T3.

“There is no evidence that combination therapy is harmful if it is done properly. As long as we don’t make our patient thyrotoxic, I don’t see any untoward effect,” Celi says. There is ample evidence that T3 given in 5 to 10 microgram quantities is safe and does not cause the problems seen with higher doses, such as atrial fibrillation. In fact, studies have shown that patients receiving T3 can have lower cholesterol and greater weight loss compared with those on T4.

Dangers of Self-Treatment

But an additional reason to respond to patients’ concerns is the ease with which they can turn to the internet to find alternative “experts” and supplements marketed to boost their thyroids. In a study published in Thyroid in 2013, researchers who tested 10 over-the-counter supplements marketed for “thyroid support” found that most “contained clinically relevant amounts of T4 and T3, some of which exceeded common treatment doses for hypothyroidism.”

Celi recently had a patient who presented with multi-organ failure and a huge amount of T3 in her blood after taking large amounts of one such supplement. She was taking dollops any time she felt the need of an internet-purchased concoction that had fine print on its label reading “not for human consumption.”

“Patients can seek alternative paths that can lead to severe harm. We need to find a middle ground where we can work with patients. Just denying the existence of their problems is not going to help anybody.” – Francesco S. Celi, MD, MHSc, chair, Division of Endocrinology, Diabetes, and Metabolism, Virginia Commonwealth University, Richmond, Va.

“Patients can seek alternative paths that can lead to severe harm. We need to find a middle ground where we can work with patients. Just denying the existence of their problems is not going to help anybody,” he says.

Designing a Trial

As part of the increased attention the thyroid community is giving to combination therapy, Bianco and Celi participated in a special session to discuss the evidence at last fall’s American Thyroid Association meeting that was co-sponsored by the European Thyroid Association and the British Thyroid Association. One goal of that session was to produce a consensus statement about the design of future clinical trials of combination therapy — based on the belief that there could be a subset of patients who could potentially benefit from combination therapy, but that past trials have not been designed to identify them.

A confounding factor in creating such a trial — and in treating these patients — is the nonspecific nature of their symptoms. But however vague to the clinician, the patients think they are real, and want them to be taken seriously.

Seaborg is a freelance writer based in Charlottesville, Va. In the December issue, he wrote about the underlying threats of primary aldosteronism



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