OBJECTIVE: In Graves' hyperthyroidism treated with antithyroid drugs (ATD), the overall relapse rate reaches 30-50% following ATD discontinuation. Conflicting results have previously been reported with regard to the usefulness of combining ATD with thyroxine (l-T4), and thereafter maintaining l-T4 treatment after ATD withdrawal. Also, clinicians are in search of useful parameters to predict the risk of a recurrence of hyperthyroidism after ATD treatment. DESIGN: Eighty-two consecutive patients (70 women and 12 men; mean age 36 years) with a first episode of Graves' hyperthyroidism were investigated prospectively; they were treated with ATD for a total of 15 months, combined with l-T4 (for at least 12 months) after they had reached euthyroidism, with the aim of maintaining serum TSH below 2.5 mU/l during the combined therapy. Following ATD discontinuation, the patients were randomly assigned (double-blind placebo-controlled trial) to taking 100 microg/day l-T4 (vs placebo) for an additional year. METHODS: The following determinations were carried out at initial diagnosis: serum total T4 and tri-iodothyronine (T3), free T4 and T3, TSH, TSH-receptor antibodies (TSHR-Ab), thyroid scintigraphy and echography. During ATD treatment, serum free T4 and T3 and TSH concentrations were recorded after 1 (optional), 2, 4, 6, 9, 12 and 15 months, and echography at the end of ATD treatment. During the randomized trial, serum free T4 and T3 and TSH concentrations were checked every 3 months (or until a recurrence). TSHR-Ab titers were measured at initial diagnosis, after 6 months with ATD, and at the end of ATD treatment. RESULTS: l-T4 administration, both during and after ATD treatment, did not improve the final outcome and recurrence rates were similar in placebo and l-T4-treated patients (30%). Two parameters were identified that might be useful to help predict recurrence risks after ATD: (i) positive TSHR-Ab (at the end of ATD treatment) was significantly associated with a greatly increased recurrence risk; and (ii) despite the relatively small number of patients who were smokers, regular cigarette smoking was shown, for the first time, to be significantly associated with an increased recurrence risk. Also, the deleterious effect of smoking was shown to manifest its impact independently of TSHR-Ab titers at the end of ATD treatment. Thus, compared with the overall 30% recurrence risk, non-smoking patients with a negative TSHR-Ab (at the end of ATD) had a lower (18%) recurrence risk; smoking patients with negative TSHR-Ab (at the end of ATD) had a 57% recurrence risk; non-smoking patients with positive TSHR-Ab (at the end of ATD) had a high (86%) recurrence risk; the recurrence risk was 100% in those few patients who both smoked and maintained a positive TSHR-Ab at the end of ATD treatment. CONCLUSIONS: The present study confirmed that l-T4 administration during and after ATD withdrawal did not improve remission rate. Two factors, namely positive TSHR-Ab at the end of ATD treatment and regular smoking habits may represent clinically useful (albeit not absolute) predictors of the risk of recurrence in patients with Graves' hyperthyroidism treated with ATD. However, due to the relatively small number of smoking patients in the present cohort, this conclusion needs to be confirmed by a larger study.
JA Verhelst, AM Pedroncelli, R Abs, M Montini, MV Vandeweghe, G Albani, D Maiter, MD Pagani, JJ Legros, D Gianola, M Bex, K Poppe, J Mockel and G Pagani
OBJECTIVE: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.