Is Thyroid Replacement Optimum With Levothyroxine? Maybe Not for Everyone

Gregory W. Rutecki, MD

I do not think I have reviewed a Top Paper from the “History of Medicine” feature in the Annals of Internal Medicine before, but here we go.1

Have you treated those people with hypothyroidism who are restored to a therapeutically appropriate thyrotropin (thyroid-stimulating hormone, or TSH) level with levothyroxine replacement therapy but who are not satisfied with the way they feel? Well, 10% to 15% of the people treated with levothyroxine end up this way, some with continuing neurocognitive complaints.2 The authors of this Top Paper apply history to make a critical therapeutic point about the unmet biologic need for triiodothyronine (T3).

A few observations about the history of thyroid replacement for hypothyroidism:

  1. Levothyroxine is more of a Johnny-come-lately. In 1965, 80% of thyroid replacement prescriptions were for natural thyroid products such as desiccated thyroid. When thyroxine (T4) hit the scene, it was justified by the discovery of peripheral T4 to T3 conversion.
  2. T4 replacement suppressed TSH and normalized both T4 and T3 levels, but at the expense of an elevated T4 to T3 ratio. More on the ratio later, but T4 became the standard of care.
  3. Other markers for bona fide thyroid replacement with T4 therapy did not suggest complete corrections of hypothyroidism. Lipids did not return to normal levels. In animal studies, the brain, liver, and skeletal muscle tissues of T4-treated hypothyroid animals continued to exhibit markers of hypothyroidism.
  4. Well, the elevated T4 to T3 ratio impairs systemic T3 production by downregulating a deiodinase pathway. With solo T4 replacement, T3 levels may not return to their pre-hypothyroid state.
  5. A specific gene in some hypothyroid patients (DIO2), a type 2 iodothyronine deiodinase gene, improves their hypothyroid symptoms with replacement of T4 and T3.

The combination approach has not completely changed the existing guidelines for thyroid replacement therapy. But acknowledgement of the fact that some patients benefit from both T3 and T4 has appeared in hypothyroid treatment guidelines issued by the European Thyroid Association and the American Thyroid Association. 

I will be listening more carefully to my patients who continue to experience hypothyroid symptoms while on T4 replacement.

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the Consultant editorial board.


  1. McAninch EA, Bianco AC. The history and future of treatment of hypothyroidism. Ann Intern Med. 2016;164(1):50-56.
  2. Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011;6(8):e22552. doi:10.1371/journal.pone.0022552.