Reduction of Thyroid Nodule Volume by Levothyroxine and Iodine Alone and in Combination: A Randomized, Placebo-Controlled Trial

CONTEXT: Nodular goiter is common worldwide, but there is still debate over the medical treatment. OBJECTIVE: The objective of the study was the measurement of the effect of a treatment with (nonsuppressive) T(4), iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid. DESIGN: This was a multicenter, randomized, double-blind trial in patients with nodular goiter in Germany [LISA (Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie) trial]. SETTING: The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practices. PARTICIPANTS: One thousand twenty-four consecutively screened and centrally randomized euthyroid patients aged 18–65 yr with one or more thyroid nodules (minimal diameter 10 mm) participated in the study. INTERVENTION: Intervention included placebo, iodine (I), T(4), or T(4)+I for 1 yr. T(4) doses were adapted for a TSH target range of 0.2–0.8 mU/liter. OUTCOME MEASURES: The primary end point was percent volume reduction of all nodules measured by ultrasound, and the main secondary end point was a change in goiter volume. RESULTS: Nodule volume reductions were −17.3% [95% confidence interval (CI) −24.8/−9.0%, P < 0.001] in the T(4)+I group, −7.3% (95% CI −15.0/+1.2%, P = 0.201) in the T(4) group, and −4.0% (95% CI −11.4/+4.2%, P = 0.328) in the I group as compared with placebo. In direct comparison, the T(4)+I therapy was significantly superior to T(4) (P = 0.018) or I (P = 0.003). Thyroid volume reductions were −7.9% (95% CI −11.8/−3.9%, P < 0.001), −5.2% (95% CI −8.7/−1.6%, P = 0.024) and −2.5% (95% CI −6.2/+1.4%, P = 0.207), respectively. The T(4)+I therapy was significantly superior to I (P = 0.034) but not to T(4) (P = 0.190). CONCLUSION: In a region with a sufficient iodine supply, a 1-yr therapy with a combination of I and T(4) with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo.