Thyroxine monotherapy restores serum T3 levels

TOPIC: Thyroxine replacement therapy

Title: Serum T3 levels in athyreotic individuals during thyroxine therapy.

Authors: Jonklaas J, Davidson B, Bhagat S, & Soldin SJ.

Reference: Journal of the American Medical Association 20: 769-777, 2008



Some hypothyroid patients on thyroxine (LT4) therapy report a variety of symptoms including poor mood, lethargy, and cognitive impairment despite normal serum TSH levels. It has been proposed that one explanation may be that serum T3 values never reach normal values with LT4 monotherapy.


To determine whether T3 levels in patients with LT4 therapy were truly lower than in the same patients with native thyroid function.


A prospective study was conducted between January 2004 and June 2007 of 50 euthyroid study subjects aged 18-65 years who were scheduled for total thyroidectomy for benign goiter, nodules suspicious for cancer, or thyroid cancer. Postop, patients were given LT4, with target TSH normal for those with benign disease and suppressed for those with cancer.

Main Outcome Measures

T4, T3, and TSH levels were measured twice preop and twice postop.


By the end of the study, there were no significant decreases in T3 concentrations in patients receiving LT4 therapy compared with their prethyroidectomy T3 levels. However, free T4 concentrations were significantly higher in patients treated with LT4 therapy, compared with their native free T4 levels. Serum TSH values of 4.5 mIU/L or less were achieved in 94% of patients by the end of the study. The T3 concentrations were lower in the subgroup of patients whose therapy had not resulted in a TSH of 4.5 mIU/L or less (p <0.001).


In this study, normal T3 levels were achieved with traditional LT4 therapy alone in patients who had undergone near-total thyroidectomy, suggesting that T3 administration is not necessary to maintain serum T3 values at their endogenous pre-thyroidectomy levels.


Although the vast majority of hypothyroid patients on thyroxine (LT4) therapy alone do and feel well, a small group of patients report symptoms despite normal thyroid function. While it has been difficult to explain this observation, some have suggested that subnormal T3 levels in T4-treated hypothyroid patients may be causally important. It has been pointed out that while T4 produces 80% of circulating T3, hypothyroid patients lack the other 20% of T3 which comes directly from the thyroid. Thus, at least theoretically, replacement therapy with T4 and T3 should be preferred to T4 monotherapy. Jonklaas et al. have performed a nice and important study to answer whether T4 therapy will restore serum T3 values to normal. They measured and compared T4, T3, and TSH levels in a group of subjects with benign and malignant thyroid nodules, before and after total thyroidectomy. Postop T4 and T3 levels were measured while the subjects were receiving T4 therapy. The authors report that in most (but not all) patients, preop and postop T3 levels were similar when serum TSH values were also in the normal range. The study suggests that T4 therapy alone can result in normal T3 levels in patients undergoing thyroidectomy. Additionally, any symptom of hypothyroidism is likely not caused by T3 deficiency. So, why should T4-treated hypothyroid patients report poor mood or memory, weight gain, or other symptoms when they are biochemically euthyroid? The present study clearly shows that such symptoms are not caused by inadequate serum T3 levels and that T4-only therapy will restore T3 to pretreatment values. We must look elsewhere to explain persistence of these symptoms.

Summary and Commentary prepared by Mahmood Gharib & Hossein Gharib (Related to Chapter 9 of TDM)

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