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New Insight on Levothyroxine Hypothyroidism Monotherapy

Nov 6, 2015

Studies suggest therapy insufficient for treatment of hypothyroidism.

Since the 19th century, thyroid hormone replacement therapy, especially levothyroxine monotherapy, has been the standard treatment for hypothyroidism. Recent clinical data suggests that the chemical composition of levothyroxine monotherapy does not normalize serum T3 concentrations or universally restore clinical euthyroidism, and a new treatment plan is needed.


In the 1970s, clinicians set the normalization of serum TSH as the treatment target. With this goal, levothyroxine monotherapy became the preferred treatment due to its safety profile, its ability to normalize serum TSH, and symptomatic remission. However, about 12% of patients reported to have residual symptoms of hypothyroidism when on that treatment. Investigators discovered that levothyroxine monotherapy may result in relative T3 deficiency, lipid abnormalities can persist, the serum T4:T3 ratio is raised, and gene expression profiles were not corrected in rats on levothyroxine monotherapy with normal serum TSH.

These studies discovered that these variables can be corrected with continuous administration of liothyronine plus levothyroxine. In a recent large clinical trial that compared patients with the genetic factor, Thr92Ala D2, polymorphism receiving combination therapy vs levothyroxine alone, that patient’s well-being improves with the combination therapy. These findings also suggest that this genetic factor is a potential risk for impaired cognition, and a personalized medicine approach may be needed.

With new findings and a better understanding of the mechanism underlying the inability of levothyroxine monotherapy to normalize serum T3 in patients with normal serum TSH, it is important that future investigations concentrating on low serum T3 or high T4:T3 ratio are done. It is also highly suggested that high-quality randomized controlled clinical trials are conducted to assess whether patients with Thr92Ala D2 polymorphism have a unique response to combination therapy. With better understanding and new findings, a new treatment strategy is foreseen in the near future.

Practice Pearls:

  • New finding suggest that levothyroxine monotherapy does not deliver enough therapy for the treatment of hypothyroidism.
  • A combination of liothyronine and levothyroxine has shown superiority in rats
  • Patients with gene Thr92Ala polymorphism may respond better to a combination treatment regimen.

“New insights into the Variable Effectiveness of Levothyroxine Monotherapy for Hypothyrodism.” The Lancet 3 (2015):756-57. The Lancet.Web.2 Oct.2015. <www.thelancet.com/diabetes-endocrinology>