Thyroid hormone replacement therapy in primary hypothyroidism:: A Randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone

Background: Substituting part of the dose of L-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results. Objective: To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland. Design: Randomized, double-blind, crossover trial. Setting: Academic research hospital. Participants: 28 women with overt primary hypothyroidism. Intervention: Crossover trial comparing treatment with L-thyroxine, 100 mu g/d (standard treatment), versus treatment with L-thyroxine, 75 mu g/d, plus liothyronine, 5 mu g/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 mu g/d, plus liothyronine, 7.5 mu g/d (add-on combination treatment), for a final 8-week add-on period. Measurements: Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes. Results: Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroidstimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015). Limitations: Treatment with L-thyroxine, 87.5 mu g/d, plus liothyronine, 7.5 mu g/d, was an add-on regimen and was not randomized. Conclusions: Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over L-thyroxine alone, yet patients prefer combination treatment.