Study Shows that the Addition of T3 is Superior to Levothyroxine/T4-Only

Thyroid Treatment for Hypothyroidism

Positive news for thyroid patients: a study published in a highly respected and reputable endocrinology journal says that the combination of T4/T3 is superior to T4 only/levothyroxine treatment for hypothyroidism! Here are the details.

The groundbreaking study reported on in the European Journal of Endocrinology, looked at the controversial issue of treatment with synthetic T3 as a supplement to T4-only (levothyroxine) therapy for hypothyroidism.

Some studies going back more than a decade have shown the superiority of the combination therapy. Other studies, however, found no difference. The inconsistency of these research findings on T3 has led some experts -- in particular, those who are biased in favor of levothyroxine-only therapy -- to conclude that there is no benefit to the addition of T3. (Some of those same "experts" even made a major logical leap, and erroneously concluded that levothyroxine/T4-only therapy is superior to T4/T3 combination therapy.)

In any case, in the new research, Danish researchers conducted a double-blind, randomized cross-over study -- which is considered the gold standard format for research -- of 59 patients. In the patient group, 50 micrograms of the usual T4 dose was replaced with either 20 mcg of T3 or 50 mcg of T4 for 12 weeks. The patients then did the "cross-over," doing the opposite for another 12 weeks.

The T4 dose was regulated if needed to keep the TSH levels stable.

Tests for quality of life (QOL) and depression were performed at the start, and after both of the 12-week treatment periods. The quality of life and psychological factors evaluated included, among other factors: general health, social functioning, mental health, vitality, sensitivity, depression, and anxiety.

What the researchers found was that among the patients -- 55 of whom were women -- there were significant differences in 7 out of 11 of the QOL and depression scores, showing a positive effect related to combination T4/T3 therapy.

A total of 49% of the patients preferred the combination treatment, and only 15% preferred levothyroxine-only treatment.

The researchers concluded that, in a study where TSH levels were kept consistent, the T4/T3 combination therapy that included 20 mcg of T3 daily was superior to levothyroxine-only treatment, when evaluating for a number of quality of life measurements, depression and anxiety scales, and patient preference.

Doctors often point to the risk of side effects with T3 therapy as a reason not to use T3, but this study showed that there was no difference with regard to side effects. According to the authors, during the T4/T3 combination therapy, five people experienced side effects including palpitations, excessive sweating, and psychological instability.

During the T4-only therapy, nine people reported the same side effects.

Interestingly, the Danish researchers pointed out problems with some of the previous studies of T4/T3 therapies that had not found any benefit to T3 treatment, saying: "the studies included in the meta-analysis were a mixture of different patient groups, including patients with previous thyroid cancer, autoimmune hypothyroidism, and subclinical as well as overt hypothyroidism."

And, according to the Danish researchers, in one of the key studies, "...[the] authors were unable to keep serum TSH levels at a similar level in the two treatment groups, mean serum TSH being 3 in the combination group and 1.5 mU/l in the monotherapy group.

The researchers have said that their study suggests that a subgroup of patients appear to benefit from the combined T4/T3 therapy. In particular, they suggest that there may be physiologic reasons why the subgroup responds to -- or needs -- the T3, specifically, that:

...a recently identified polymorphism in the gene coding for the type two deiodinase, the enzyme responsible for the regulation of T3 availability to the tissues, has been proposed in order to help identifying subgroups more likely to benefit from T4/T3 combination therapy. Another polymorphism, located in OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, has been associated with fatigue and depression.

Famed Dutch Endocrinologist Wilmar Wiersinga Says Sustained Release T3 May be Best, Some People May Have Genetic Propensity to Do Better on T3

Dutch endocrinologist Wilmar Wiersinga wrote an accompanying editorial, titled "Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?"

According to Dr. Wiersinga, some previous studies had concluded that there is no benefit to adding T3. Yet, the fact that, according to Wiersinga, as many as 10% of hypothyroid patients are dissatisfied with how they feel on what doctors would call an "adequate dose" of levothyroxine replacement led to the publication of the Danish study.

The editorial, which is published in full-online, points to flaws in the previous studies and analyses of T4/T3 combination therapy. Dr. Wiersinga concludes that there are two strong reasons to conduct additional randomized controlled trials comparing levothyroxine/T4 only treatment monotherapy, to T4/T3 combination therapy:

First, trials so far have been largely unsuccessful in mimicking physiological serum FT4-FT3 ratios throughout 24 h. The development of sustained-release T3 preparations might be essential for reaching the goal of 'physiological' thyroid hormone replacement. Secondly, an increasing number of polymorphisms in deiodinases and thyroid hormone transporters are associated with psychological well-being, depression, fatigue, and preference for combination therapy. Could it be that subjects not satisfied with monotherapy are frequent carriers of these polymorphisms, and will have a better response to combination therapy?

According to Dr. Wiersinga, development of a sustained-release T3 preparation, given as a single nighttime dose (together with levothyroxine once daily) might best maintain physiological ratios of Free T4 and Free T3 in some thyroid patients over a 24-hour period.

Note: So let's just recap this again. Half the patients preferred the T4/T3 combination -- only 15% preferred levothyroxine-only, AND, quality of life and other factors were improved. AND, the T4/T3 therapy had no more side effects than the T4-alone. (In fact, in this study, the T4-only therapy caused MORE side effects.) I anticipate that some of the same so-called thyroid experts -- who frequently are also on the payroll for the levothyroxine manufacturers -- are probably going to fall all over themselves trying to explain away the findings, and it's going to be fun watching them try!

The actual journal article in its entirety is fascinating reading, but unfortunately, it's not posted on the Internet in full. You can, however, purchase a copy online for $25 at the European Journal of Endocrinology website. This is definitely one that you want your doctor to read as well, so be sure to let him or her know to get a copy as well. Frankly, it might even be worth it to buy a copy to GIVE to your doctor, if he/she isn't willing to learn about new thyroid developments.

More Information on T4-Only Vs. T4/T3 Combination Treatment for Hypothyroidism


Birte Nygaard, Ebbe Winther Jensen, Jan Kvetny, Anne Jarløv and Jens Faber. "Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study," European Journal of Endocrinology, Vol 161, Issue 6, 895-902, December 2009 Abstract, (Full text ($25))

Wiersinga, Wilmar "Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?" European Journal of Endocrinology, Vol 161, Issue 6, 955-959. Full text (free)

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