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Submitted on October 26, 2004
Accepted on February 1, 2005
Departments of Endocrinology and Metabolism, Psychiatry, Cardiology, Clinical Chemistryand General Practice, Academic Medical Centre, University of Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: b.c.appelhof{at}amc.uva.nl.
Introduction: Controversy remains about the value of combined treatment with levothyroxine (LT4) and liothyronine (LT3) compared with LT4 alone in primary hypothyroidism. We compared combined treatment with LT4 and LT3 in a ratio of 5:1 or 10:1 with LT4 monotherapy.
Methods: We conducted a double-blind, randomized, controlled trial in 141 patients (18-70 yr) with primary autoimmune hypothyroidism, recruited via general practitioners. Inclusion criteria: LT4 treatment for 
6 months, a stable dose for 6 weeks and serum TSH levels between 0,11-4,0 µU/ml (mU/L). Randomisation groups: 1) continuation of LT4 (n = 48), 2)LT4/LT3, ratio 10:1 (n = 46), 3) LT4/LT3, ratio 5:1 (n = 47). Subjective preference of study medication after 15 weeks compared with usual LT4 was the primary outcome measure. Secondary outcomes included scores questionnaires on mood, fatigue, psychological symptoms and a substantial set of neurocognitive tests.
Results: Study medication was preferred to usual treatment by 29,2%, 41,3% and 52,2% in the LT4, 10:1 ratio and 5:1 ratio groups respectively (Chi square test for trend, P = 0.024). This linear trend was not substantiated by results on any of the secondary outcome measures: scores on questionnaires and neurocognitive tests consistently ameliorated, but the amelioration was not different between the treatment groups. Median endpoint serum TSH was 0.64 µU/ml (mU/L), 0.35 µU/ml (mU/L) and 0.07 µU/ml (mU/L) respectively (Anova on ln(TSH) for linear trend P < 0.01). Mean bodyweight change was +0.1 kg, -0.5 kg and -1.7 kg respectively (Anova for trend P = 0.01). Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT4/LT3 therapy, 44% had serum TSH <0.11 µU/ml (mU/L).
Conclusion: Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy. Decrease in bodyweight was associated with satisfaction with study medication.
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