DESPITE THE FACT that radioiodine ( 131 I) therapy is

Transcription

1 X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(8): Printed in U.S.A. Copyright 2006 by The Endocrine Society doi: /jc Continuous Methimazole Therapy and Its Effect on the Cure Rate of Hyperthyroidism Using Radioactive Iodine: An Evaluation by a Randomized Trial Steen Joop Bonnema, Finn Noe Bennedbæk, Annegrete Veje, Jens Marving, and Laszlo Hegedüs Departments of Endocrinology and Metabolism (S.J.B., F.N.B., L.H.) and Nuclear Medicine (A.V., J.M.), Odense University Hospital, DK-5000 Odense C, Denmark Background: A randomized clinical trial was performed to clarify whether continuous use of methimazole (MTZ) during radioiodine ( 131 I) therapy influences the final outcome of this therapy. Design: Consecutive patients with Graves disease (n 30) or a toxic nodular goiter (n 45) were rendered euthyroid by MTZ and randomized to stop MTZ 8 d before 131 I( MTZ; n 36) or to continue MTZ until 4 wk after 131 I( MTZ; n 39). Calculation of the 131 I activity included an assessment of the 131 I half-life and the thyroid volume. Results: The 24-h thyroid 131 I uptake was lower in the MTZ group than in the MTZ group ( % vs %, respectively; P 0.001). At 3 wk after therapy, no significant change in serum free T 4 index was observed in the MTZ group ( vs nmol/liter at baseline; P 0.26), contrasting an increase in the MTZ group ( vs nmol/liter; P 0.001). The number of DESPITE THE FACT that radioiodine ( 131 I) therapy is widely used for treatment of hyperthyroid disorders, there is no consensus regarding 131 I dose calculation (1) and the use of antithyroid drugs in conjunction with the therapy. Antithyroid drugs are usually safe and rapidly result in euthyroidism (2). Because relapse of the hyperthyroidism often follows withdrawal of the drug (2, 3), 131 I comes in as the first or second line of therapy. If rapid access to nuclear medicine facilities is available, antithyroid premedication is probably unnecessary in young and healthy individuals (4, 5). However, many physicians prefer to render their patients euthyroid by antithyroid drugs before 131 I therapy, probably to avoid 131 I- induced thyroid storm, which, however, is rarely encountered. Many studies (6 21) have been conducted over the years to evaluate whether antithyroid drugs in conjunction with 131 I affect the outcome. The results have to some extent been conflicting. Retrospective studies (9 14), carrying the risk of being influenced by selection bias, have shown that methimazole (MTZ) (or the prodrug carbimazole) diminishes the effect of 131 I. This observation, however, has not been confirmed in recent prospective trials (15 17), whereas studies on thiouracils have First Published Online May 30, 2006 Abbreviations: 131 I, Radioiodine; MTZ, methimazole; s-ft3, serum free T 3 ; s-ft4, serum free T 4 ; s-tsh, serum TSH; TPOabs, thyroid peroxidase antibodies. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community. cured patients was 17 (44%) and 22 (61%) in the MTZ and MTZ groups, respectively (P 0.17). Cured patients tended to have a lower 24-h thyroid 131 I uptake ( % vs %; P 0.09). By adjusting for a possible interfactorial relationship through a regression analysis (variables: randomization, 24- and 96-h thyroid 131 I uptake, type and duration of disease, age, gender, presence of antithyroid peroxidase antibodies, thyroid volume, dose of MTZ), only the continuous use of MTZ correlated with treatment failure (P 0.006), whereas a low 24-h thyroid 131 I uptake predicted a better outcome (P 0.006). Conclusion: Continuous use of MTZ hinders an excessive increase of the thyroid hormones during 131 I therapy of hyperthyroid diseases. However, such a strategy seems to reduce the final cure rate, although this adverse effect paradoxically is attenuated by the concomitant reduction of the thyroid 131 I uptake. (J Clin Endocrinol Metab 91: , 2006) been more consistent (18 20). Although it is widely accepted that antithyroid drugs have radioprotective properties, it seems to be an area with great complexity involving several factors. If antithyroid drugs are used, various regimens are applied. The drug is usually paused shortly before the 131 I administration to augment the thyroid 131 I uptake and probably also to avoid any possible radioprotective effect. At some centers, the antithyroid drug is given simultaneously with 131 I therapy to maintain euthyroidism until the effect of the 131 I therapy sets in. According to retrospective studies, such a strategy leads to a higher number of treatment failures than if the drug is discontinued (12, 13). Considering the contradictory results from earlier studies, we decided to challenge this view by a randomized trial. Patients Patients and Methods We enrolled consecutively patients with recurrent Graves disease or toxic nodular goiter who were referred for 131 I therapy at our institution. Criteria excluding patients from 131 I therapy were age less than 18 yr, pregnancy or anticipation of pregnancy, lactation, suspicion of thyroid malignancy, large or partly intrathoracic goiter, and moderate/severe Graves ophthalmopathy. Reasons for not being eligible for the study were previous 131 I therapy, propylthiouracil treatment within the last 3 months, known allergic reaction to MTZ, or physical or psychiatric disabilities suggestive of difficulties in completing follow-up. Design At inclusion, all patients were on MTZ and were randomized (computer-generated numbers in closed envelopes) either to stop MTZ 8 d before 131 I therapy ( MTZ), without resumption of the drug afterward, 2946

2 Bonnema et al. MTZ during 131 I Therapy J Clin Endocrinol Metab, August 2006, 91(8): or to continue MTZ during the 131 I therapy ( MTZ). In both groups, the dose of MTZ was adjusted guided by the thyroid function tests, and the patients were referred to 131 I therapy when stable euthyroidism was obtained [i.e. two consecutive sets of serum free T 4 (s-ft4) index and serum free T 3 (s-ft3) index within the normal range]. In the post- 131 I period, the thyroid function was monitored after 3, 6, and 12 wk, and thereafter every 3 months for a follow-up period of 1 yr. If the patient had hyperthyroid symptoms in the early post- 131 I period, these were managed by -blockers in both groups. In the MTZ group, MTZ was discontinued at 3 wk post- 131 I if euthyroidism or hypothyroidism was present at this time. In case hyperthyroidism recurred beyond 3 wk post- 131 I, MTZ was reinstituted in both groups, and this medication was subsequently tapered during the follow-up period. If this was unsuccessful, a second 131 I dose was eventually administered at the earliest 9 months after the initial therapy. Hypothyroidism was treated with levothyroxine. If a low dose of levothyroxine was required, a trial of discontinuation was made within the follow-up period to ensure that the hypothyroidism was not transient. The patients were classified as being hypothyroid, euthyroid, or hyperthyroid according to their thyroid function at the end of follow-up or before a second 131 I dose was administered. Euthyroidism was defined as s-ft4 index and s-ft3 index within the normal range; hypothyroidism was defined as serum TSH (s-tsh) above the normal range, with or without s-ft4 index below the normal range; and hyperthyroidism was defined as s-tsh below the normal range and s-ft4 index or s-ft3 index above the normal range. The study was approved by the local Ethics Committee, and it was registered at All patients provided signed informed consent. Methods and 131 I therapy s-tsh (reference interval, mu/liter) was measured using a time-resolved fluoroimmunometric assay (AutoDELFIA human TSH ultra, PerkinElmer/Wallac, Turku, Finland). Serum T 4 (reference interval, nmol/liter) and T 3 (reference interval, nmol/liter) were determined by RIA (Diagnostic Products Corp., Los Angeles, CA, and Johnson & Johnson, Amersham, Pharmacia Biotech, Aylesbury, UK, respectively). s-ft4 and s-ft3 indexes were calculated multiplying the total values by the percent T 3 resin uptake (reference interval, arbitrary units). Thyroid peroxidase antibodies (TPOabs) were measured by a solid phase, two step, time-resolved fluoroimmunoassay (AutoDELFIA TPOab kit, PerkinElmer/Wallac). Values above 60 U/ml are regarded as positive. TSH receptor antibodies were measured using a radio receptor assay (DYNOtest TRAK human kit, BRAHMS Diagnostica Gmbh, Berlin, Germany). TRab values less than 1 IU/liter are regarded as negative, values more than 2 IU/liter as positive. Thyroid 99m Tc-scintigraphy was performed at baseline on high-resolution -camera equipment. Thyroid ultrasound was performed at baseline and 1 yr after the 131 I therapy by trained endocrinologists (S.J.B., F.N.B., L.H.), and it included planimetric volume estimation using precise and accurate equipment (type 1846, Brüel & Kjær, Copenhagen, Denmark). This method has an intra- and interobserver coefficient of variation of 5 and 7%, respectively (22). A classification into Graves or nodular thyroid disease was based on the clinical presentation, the results of the imaging methods, and serum TRab. 131 I was given as a single oral dose on an outpatient basis targeting the thyroid dose at 100 Gy. Because it was anticipated that ongoing MTZ treatment affected the 131 I kinetics, the calculated 131 I-activity was based on the following elaborated algorithm: Activity (MBq) thyroid volume (ml) 22.4 (days MBq/ml) source. All measurements were background corrected. 131 I therapy was given on the day of the 96-h uptake measurement. The maximum 131 I activity was restricted to 600 MBq according to the official health authority regulations. Glucocorticoids (25 mg/d prednisolone for 30 d) were routinely used in patients with previously active or present mild Graves ophthalmopathy to prevent a reactivation/worsening of the orbital inflammation. Statistical analysis Anticipating a cure rate (euthyroidism or hypothyroidism) of 80% within 1 yr in one of the randomization arms, a sample size of 29 in each group was calculated to provide 90% power to ensure detection of a difference in cure rate of at least 25% between the two groups. Baseline data are presented as mean sd or median and range if not normally distributed. 2 test, one-way ANOVA, and Mann-Whitney test (if appropriate) were used to compare baseline characteristics and for analyzing differences in outcome. A backward step-wise logistic regression analysis was employed for testing correlations. P 0.05 (two-sided) was considered statistically significant. Results Baseline characteristics During a period of 2 yr, 195 hyperthyroid patients were referred for 131 I therapy (Fig. 1). Of the 79 patients who were initially included, 40 patients were randomized to the MTZ group and 39 patients to the MTZ group. Two patients regretted their commitment after randomization but before the 131 I therapy. One patient, randomized to the MTZ group, died from a cerebral stroke shortly after the 131 I therapy, and another patient was lost to follow-up. The remaining 75 patients, 39 in the MTZ group and 36 in the MTZ group, completed follow-up (Fig. 1). Thirty individuals had Graves disease, and 45 had a toxic nodular goiter. The baseline characteristics stratified for disease and randomization are shown in Table 1. The median level of s-tsh at the time of 131 I therapy (but before discontinuation of MTZ in the MTZ group) was higher in the MTZ group than in the MTZ group (0.43 vs mu/liter; P 0.007). The median MTZ dose required to render the patient euthyroid before the 131 I therapy was /[t 1/2 (days) 24-h 131 I uptake (%)] The effective t 1/2 was calculated from the 24- and 96-h thyroid 131 I uptakes after the oral administration of 0.5 MBq 131 I (patients in the MTZ group were at this time off MTZ). The tracer 131 I dose was placed in a neck phantom, and count rate was measured at a fixed distance (30.0 cm from the detector) using a collimated 2-inch NaI(TI)-scintillation probe (Biodex Medical Systems, Inc., Shirley, NY; Atom-Lab 950), with dead-time correction. The energy window was 364 KeV 15%, and the energy solution was controlled and corrected daily with a 137 Cs test FIG. 1. Trial profile.

3 2948 J Clin Endocrinol Metab, August 2006, 91(8): Bonnema et al. MTZ during 131 I Therapy TABLE 1. Group characteristics before 131 I therapy Graves disease Toxic nodular goiter All glands (n 75) MTZ (n 19) MTZ (n 11) MTZ (n 20) MTZ (n 25) MTZ (n 39) MTZ (n 36) Type of disease (Graves 19/20 11/ disease/toxic nodular goiter) Age (yr) Gender (female/male) 18/1 9/2 19/1 23/2 37/2 32/ Thyroid volume (ml) 32 (16 65) 41 (15 123) 42 (19 91) 41 (22 98) 34 (16 91) 41 (15 123) 0.10 Presence of anti-tpoabs (n) TSH receptor antibodies (U/liter) 7.5 ( ) 10.9 ( ) nd nd s-tsh (mu/liter) 0.46 ( 6.68) 0.01 ( 1.48) 0.40 ( 4.33) 0.03 ( 4.36) 0.43 ( 6.88) 0.02 ( 4.36) s-ft3 index (nmol/liter) s-ft4 index (nmol/liter) Dose of MTZ (mg) 7.5 ( ) 5.0 ( ) 5.0 ( ) 5.0 ( ) 7.5 ( ) 5.0 ( ) 0.70 Use of steroid prophylaxis (n) 10 7 Posttherapy -blockers (n) Thyroid 24-h uptake (%) Thyroid 96-h uptake (%) I half-life (d) I activity (MBq) 233 ( ) 359 ( ) 371 ( ) 271 ( ) 267 ( ) 277 ( ) 0.58 Data represent number of patients, mean SD, or median (range). nd, Not detectable. a Between-group difference in all glands. P a mg (range, mg) in the MTZ group and 5.0 mg (range, mg) in the MTZ group (P 0.70). The 24-h 131 I thyroid uptake was % in the MTZ group and % in the MTZ group (P 0.001). The betweengroup difference in the 96-h 131 I thyroid uptake was also marked (Table 1). The changes in the 131 I kinetics were slightly more pronounced among patients with Graves disease because there was a significant between-group difference in half-life [ d ( MTZ) vs d ( MTZ); P 0.012], not found among patients with toxic nodular goiter ( d vs d; P 0.43). The median 131 I activity administered was 267 MBq (range, MBq) in the MTZ group and 277 MBq (range, MBq) in the MTZ group (P 0.58). Due to a calculated 131 I activity exceeding the maximum of 600 MBq, the administered activity was reduced and set at this limit in four patients in each group. Ten patients in the MTZ group and seven patients in the MTZ group received glucocorticoids during the 131 I therapy as protection against 131 I-induced ophthalmopathy. Outcome At baseline, the s-ft4 index was similar in the two groups ( MTZ, nmol/liter; MTZ, nmol/liter; P 0.90). At 3 wk after 131 I therapy, no significant change in s-ft4 index was observed in the MTZ group ( nmol/ liter; P 0.26), contrasting an increase to nmol/ liter in the MTZ group (P within group; P between groups, see Fig. 2). The between-group difference was insignificant at 6 wk (P 0.57) but clearly higher than at baseline ( MTZ group, nmol/liter, P 0.002; MTZ group, nmol/liter, P 0.001, Fig. 2). Similar patterns were found for s-ft3 index (data not shown). In the posttherapy period, only four patients needed -blockade (two in each group). After 1 yr of follow-up, 34 patients were classified as euthyroid, five developed permanent hypothyroidism, and the remaining 36 individuals had recurrence of the hyperthyroidism (Table 2). One patient in each randomization group had a subnormal s-tsh with normal values of s-ft4 index and s-ft3 index (were classified as being euthyroid). Eight patients (four in each group) were treated with MTZ beyond 6 wk post- 131 I therapy due to hyperthyroidism, but subsequent withdrawal of the drug was successful leaving the patient euthyroid, thus indicating a late onset effect of the 131 I therapy. Classifying the outcome into two categories, cured (euthyroidism or hypothyroidism) or not cured (recurrence), treatment failure was more frequently encountered among patients with Graves disease than among those with a toxic nodular goiter (18 of 30 vs. 18 of 45; P 0.10). The number of cured patients was 17 (44%) and 22 (61%) in the MTZ and MTZ groups, respectively (P 0.17). In addition, patients who were cured tended to have a lower 24-h thyroid 131 I uptake than those who were not cured ( % vs %; P 0.09). This tendency was FIG. 2. Mean s-ft4 index in the period before and early after the 131 I therapy. In the MTZ group, MTZ was discontinued 8 d before 131 I therapy. The increase at 6 wk in the MTZ group is mainly explained by the fact that MTZ was discontinued at 3 wk if thyroid function tests at this time showed euthyroidism. Gray area, Normal range. Bars, SEM. *,P by between-group comparisons.

4 Bonnema et al. MTZ during 131 I Therapy J Clin Endocrinol Metab, August 2006, 91(8): TABLE 2. Thyroid function 1 yr after 131 I therapy according to the randomization MTZ (n 39) MTZ (n 36) P Thyroid function (H/E/R) All glands (n 75) 2/15/22 3/19/14 5/39/56% 8/53/39% Recurrence/cured All glands (n 75) 22/17 14/ /44% 39/61% Graves disease (n 30) 12/7 6/ /37% 55/45% Toxic nodular goiter (n 45) 10/10 8/ /50% 32/68% Data represent numbers (upper line) and percentages (lower line) of patients in each of the three categories (H, hypothyroidism; E, euthyroidism; R, recurrence). Cured is defined as obtainment of either euthyroidism or hypothyroidism. apparent also when stratified for randomization ( MTZ group, % vs %, P 0.09; MTZ group, % vs %, P 0.001) or type of disease (Graves disease, % vs %, P 0.27; toxic nodular goiter, % vs %, P 0.30). Data on the 96-h 131 I uptake showed the same pattern as for the 24-h 131 I uptake (data not shown). Because the intervention (i.e. the continuous use of MTZ) and the thyroid 131 I uptake (very likely being affected by the intervention per se) seemed to some extent to counterbalance each other with respect to the cure rate, these variables were analyzed in a logistic regression analysis. In addition, other independent factors with putative influence on the outcome were included, i.e. age, gender, duration of the disease, initial thyroid volume, type of disease (Graves or toxic nodular goiter), dose of MTZ, and presence of anti-tpoab. By adjusting for the interfactorial relationships, with cure rate as the dependent variable, only the continuous use of MTZ turned out to have a significant adverse effect, whereas a low 24-h thyroid 131 I uptake predicted a better outcome (P 0.006, Table 3). For the cured patients (n 39), uninfluenced by a second 131 I dose, the mean thyroid volume reduction was % (sem) at the end of follow-up, without any significant difference between the MTZ and MTZ groups. TABLE 3. Key variables included in the regression analysis for prediction of the outcome of 131 I therapy All variables in the equation Coefficient SEM P Continuous use of MTZ Age Male gender Duration of disease Initial thyroid volume Presence of Graves disease Dose of MTZ Presence of anti-tpoabs Thyroid 24-h 131 I uptake Thyroid 96-h 131 I uptake By backward step-wise regression Continuous use of MTZ Thyroid 24-h 131 I uptake The dependent variable is cure rate (euthyroidism or hypothyroidism). A positive value of the coefficient is related to treatment failure. Discussion 131 I therapy of hyperthyroid diseases is frequently given after pretreatment with an antithyroid drug. In most of the previous studies within this field, thyrostatic medication is discontinued 2 14 d before 131 I administration, a strategy probably used by the majority of physicians. Only a few studies (12, 13) have dealt with the regimen in which MTZ (or the prodrug carbimazole) is continued during and after the 131 I therapy without pausing. The argument for this approach is the avoidance of a transient rise in the thyroid hormones, known to occur when antithyroid drugs are stopped before 131 I therapy (4, 5, 20). A more stable thyroid function was in fact confirmed by the present randomized trial, speaking in favor of the continuous use of MTZ during 131 I therapy. Furthermore, the extrathyroid radiation may be lowered in some patients because the amount of proteinbound 131 I in the blood is reduced (23). However, our data support the findings in earlier retrospective studies (12, 13) that such a regimen increases the risk of treatment failure. The difference in cure rate in our study, 61% if MTZ was discontinued before 131 I therapy vs. 44% with the continuous use regimen, was statistically insignificant, but it was evident that other factors influenced the outcome in a complex manner. We found that the cure rate tended to be higher among those patients with the lowest 24-h thyroid 131 I uptake. This relationship was present both among patients with Graves disease and those with a toxic nodular goiter. Like other iodine isotopes, 131 I undergoes organification in the thyroid (2), which markedly affects the 131 I kinetics. Blocking the organification by antithyroid drugs diminishes the thyroid 131 I uptake, and the half-life is altered because iodine cannot be trapped within the gland. This phenomenon has previously been demonstrated (12, 24) and was confirmed in the present study. Although we did not assess the 131 I kinetics before randomization, it is most likely that the highly significant between-group difference in the thyroid 131 I uptake was caused by the intervention (i.e. continuous use of MTZ) and does not just reflect a chance finding. Because we anticipated such impact on the 131 I kinetics, the dose calculation included not only a precise thyroid volume estimation, as well as the 24-h thyroid 131 I uptake, but also the 131 I half-life. Although such an algorithm may still be too simple considering the complex kinetics observed during ongoing antithyroid medication (25) and the influence of the shrinkage of the gland (26), an algorithm that omits the 131 I half-life systematically miscalculates the thyroid dose (27). An elaborated algorithm is probably not cost-effective in a routine setting (1), but we found it necessary in this trial investigating a drug known to affect the 131 I kinetics. Thus, all patients received approximately equal thyroid doses, apart from the few individuals in whom dose restriction was necessary. Nevertheless, the high rate of treatment failure (overall approximately 50%) clearly indicates that the thyroid dose in general should have been more than the intended 100 Gy. This suboptimal cure rate, however, allows disclosure of other factors being of importance for the outcome. Thus, MTZ on one hand reduces the 131 I uptake, which per se seems beneficial for yet unknown reasons, and on the other hand,

5 2950 J Clin Endocrinol Metab, August 2006, 91(8): Bonnema et al. MTZ during 131 I Therapy it decreases the cure rate. A regression analysis, performed to disclose the impact of each relevant factor, showed that both continuous use of MTZ and a high 24-h 131 I uptake were significantly related to a poorer outcome after 131 I therapy. Patients randomized to discontinue MTZ seem to have been slightly more hyperthyroid because baseline s-tsh was significantly lower in this group. Because the severity of hyperthyroidism usually is correlated with treatment failure after 131 I therapy (8), we may have underestimated the difference in cure rate between the two randomization arms. As in other studies (7 10, 16, 20, 21), we enrolled patients with both Graves disease and toxic nodular goiter. The role of antithyroid drugs in conjunction with 131 I therapy may be different in the two phenotypes, as indicated by one study (10). Our trial was not designed to compare the outcome in the two types of diseases, but the regression analysis showed that type of disease had no independent role in this context. It is puzzling that the negative effect by simultaneous MTZ treatment to some extent is counteracted by the reduction of the thyroid 131 I uptake. A high thyroid 131 I uptake is usually considered as a prerequisite for a successful outcome after 131 I therapy (24), and several efforts have aimed at increasing the 131 I uptake during therapy, such as an iodine-restricted diet (28), the administration of lithium (29), or hydrochlorothiazide (30). However, studies based on careful dosimetric measurements support the possibility of an inverse relationship between the thyroid 131 I uptake and the radiosensitivity of the gland (31). Another possible explanation is pretherapeutic 131 I uptake measurement resulting in some degree of stunning, a phenomenon seen with even minute radiation (32), which may be most significant in cases with high 131 I uptake. The underlying mechanisms of this seemingly paradoxical relationship between a low thyroid 131 I uptake and a high cure rate are at present obscure. Nevertheless, our results are in line with that of others (33 35), also showing a better outcome in patients with low thyroid 131 I uptake. Our study is the first, however, in which the 131 I uptake was reduced by randomized intervention. How MTZ exerts its radioprotective effect is not clear. The cell damage induced by ionizing radiation is, at least in part, mediated through the production of reactive oxygen radicals. Hyperthyroidism due to Graves disease is associated with an increased level of free oxygen radicals (36), and a lower metabolism in the thyrocyte may diminish the susceptibility to radiation. In fact, hypothyroidism in rats induced by MTZ (37) ameliorates the oxidative stress caused by inflammatory injury. Although antithyroid drugs at physiological concentrations have scavenger-like properties in human neutrophils (38), this seems to be of no great significance in a normal clinical setting (39). Whether this feature becomes important when exposed to ionizing radiation is yet unsettled. MTZ seems to play a role in the FasL-dependent apoptosis of intrathyroidal lymphocytes (40), a possible explanation for the postulated immunoregulatory properties of antithyroid drugs, but in conjunction with 131 I therapy, this may be disadvantageous. Even though continuous use of MTZ during 131 I therapy is beneficial as regards the thyroid function in the early post- 131 I period, the present randomized trial supports that an increase in treatment failure should be expected with such a regimen. Based on our study as well as other studies (15 17), we therefore recommend that if MTZ (or carbimazole) is used before 131 I therapy, the drug should be discontinued a few days before 131 I with subsequent resumption after approximately 1 wk, with or without levothyroxine, to prevent a transient hyperthyroid phase (16). Acknowledgments Received February 1, Accepted May 18, Address all correspondence and requests for reprints to: Steen J. Bonnema, M.D., Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. steen.bonnema@dadlnet.dk. This study was supported by research grants from The Agnes and Knut Mørks Foundation, The A.P. Møller Relief Foundation, and The Novo Nordisk Foundation. References 1. Kalinyak JE, McDougall IR 2003 How should the dose of iodine-131 be determined in the treatment of Graves hyperthyroidism? J Clin Endocrinol Metab 88: Cooper DS 2005 Antithyroid drugs. N Engl J Med 352: Abraham P, Avenell A, Park CM, Watson WA, Bevan JS 2005 A systematic review of drug therapy for Graves hyperthyroidism. Eur J Endocrinol 153: Andrade VA, Gross JL, Maia AL 1999 Effect of methimazole pretreatment on serum thyroid hormone levels after radioactive treatment in Graves hyperthyroidism. J Clin Endocrinol Metab 84: Burch HB, Solomon BL, Cooper DS, Ferguson P, Walpert N, Howard R 2001 The effect of antithyroid drug pretreatment on acute changes in thyroid hormone levels after 131I ablation for Graves disease. J Clin Endocrinol Metab 86: Alexander EK, Larsen PR 2002 High dose of 131I therapy for the treatment of hyperthyroidism caused by Graves disease. J Clin Endocrinol Metab 87: Velkeniers B, Cytryn R, Vanhaelst L, Jonckheer MH 1988 Treatment of hyperthyroidism with radioiodine: adjunctive therapy with antithyroid drugs reconsidered. Lancet 1: Allahabadia A, Daykin J, Sheppard MC, Gough SC, Franklyn JA 2001 Radioiodine treatment of hyperthyroidism-prognostic factors for outcome. J Clin Endocrinol Metab 86: Nygaard B, Hegedüs L, Ulriksen P, Nielsen KG, Hansen JM 1999 Radioiodine therapy for multinodular toxic goiter. Arch Intern Med 159: Körber C, Schneider P, Korber-Hafner N, Hanscheid H, Reiners C 2001 Antithyroid drugs as a factor influencing the outcome of radioiodine therapy in Graves disease and toxic nodular goitre? Eur J Nucl Med 28: Reynolds LR, Kotchen TA 1979 Antithyroid drugs and radioactive iodine. Fifteen years experience with Graves disease. Arch Intern Med 139: Clerc J, Izembart M, Dagousset F, Jais JP, Heshmati HM, Chevalier A, Leger AF, Barritault L 1993 Influence of dose selection on absorbed dose profiles in radioiodine treatment of diffuse toxic goiters in patients receiving or not receiving carbimazole. J Nucl Med 34: Sabri O, Zimny M, Schulz G, Schreckenberger M, Reinartz P, Willmes K, Buell U 1999 Success rate of radioiodine therapy in Graves disease: the influence of thyrostatic medication. J Clin Endocrinol Metab 84: Marcocci C, Gianchecchi D, Masini I, Golia F, Ceccarelli C, Bracci E, Fenzi GF, Pinchera A 1990 A reappraisal of the role of methimazole and other factors on the efficacy and outcome of radioiodine therapy of Graves hyperthyroidism. J Endocrinol Invest 13: Andrade VA, Gross JL, Maia AL 2001 The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves hyperthyroidism: one-year follow-up of a prospective, randomized study. J Clin Endocrinol Metab 86: Bonnema SJ, Bennedbæk FN, Gram J, Veje A, Marving J, Hegedüs L 2003 Resumption of methimazole after 131I therapy of hyperthyroid diseases: effect on thyroid function and volume evaluated by a randomized clinical trial. Eur J Endocrinol 149: Braga M, Walpert N, Burch HB, Solomon BL, Cooper DS 2002 The effect of methimazole on cure rates after radioiodine treatment for Graves hyperthyroidism: a randomized clinical trial. Thyroid 12: Imseis RE, Vanmiddlesworth L, Massie JD, Bush AJ, Vanmiddlesworth NR 1998 Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine-131 in hyperthyroidism. J Clin Endocrinol Metab 83:

6 Bonnema et al. MTZ during 131 I Therapy J Clin Endocrinol Metab, August 2006, 91(8): Tuttle RM, Patience T, Budd S 1995 Treatment with propylthiouracil before radioactive iodine therapy is associated with a higher treatment failure rate than therapy with radioactive iodine alone in Graves disease. Thyroid 5: Bonnema SJ, Bennedbæk FN, Veje A, Marving J, Hegedüs L 2004 Propylthiouracil before 131I therapy of hyperthyroid diseases: effect on cure rate evaluated by a randomized clinical trial. J Clin Endocrinol Metab 89: Ahmad AM, Ahmad M, Young ET 2002 Objective estimates of the probability of developing hypothyroidism following radioactive iodine treatment of thyrotoxicosis. Eur J Endocrinol 146: Hegedüs L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, Jensen G, Hansen JM 1983 The determination of thyroid volume by ultrasound and its relationship to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 56: Zanzonico PB, Becker DV, Hurley JR 2004 Enhancement of radioiodine treatment of small-pool hyperthyroidism with antithyroid drugs: kinetics and dosimetry. J Nucl Med 45: Moka D, Dietlein M, Schicha H 2002 Radioiodine therapy and thyrostatic drugs and iodine. Eur J Nucl Med Mol Imaging 29(Suppl 2):S486 S Kuenstner H, Dunkelmann A, Koch U, Groth P, Schuemichen C 2004 Recovery of radioiodine kinetics in the thyroid after discontinuation of thyrostasis. Eur J Nucl Med Mol Imaging 31(Suppl 2):S Traino AC, Di Martino F, Lazzeri M 2004 A dosimetric approach to patientspecific radioiodine treatment of Graves disease with incorporation of treatment-induced changes in thyroid mass. Med Phys 31: Berg GE, Michanek AM, Holmberg EC, Fink M 1996 Iodine-131 treatment of hyperthyroidism: significance of effective half-life measurements. J Nucl Med 37: Morris LF, Wilder MS, Waxman AD, Braunstein GD 2001 Reevaluation of the impact of a stringent low-iodine diet on ablation rates in radioiodine treatment of thyroid carcinoma. Thyroid 11: Bogazzi F, Bartalena L, Brogioni S, Scarcello G, Burelli A, Campomori A, Manetti L, Rossi G, Pinchera A, Martino E 1999 Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves hyperthyroidism. J Clin Endocrinol Metab 84: Tepmongkol S 2002 Enhancement of radioiodine uptake in hyperthyroidism with hydrochlorothiazide: a prospective randomised control study. Eur J Nucl Med Mol Imaging 29: Di Martino F, Traino AC, Brill AB, Stabin MG, Lazzer M 2002 A theoretical model for prescription of the patient-specific therapeutic activity for radioiodine therapy of Graves disease. Phys Med Biol 47: Postgard P, Himmelman J, Lindencrona U, Bhogal N, Wiberg D, Berg G, Jansson S, Nystrom E, Forssell-Aronsson E, Nilsson M 2002 Stunning of iodide transport by (131)I irradiation in cultured thyroid epithelial cells. J Nucl Med 43: Catargi B, Leprat F, Guyot M, Valli N, Ducassou D, Tabarin A 1999 Optimized radioiodine therapy of Graves disease: analysis of the delivered dose and of other possible factors affecting outcome. Eur J Endocrinol 141: Walter MA, Christ-Crain M, Eckard B, Schindler C, Nitzsche EU, Muller- Brand J, Muller B 2004 Radioiodine therapy in hyperthyroidism: inverse correlation of pretherapeutic iodine uptake level and post-therapeutic outcome. Eur J Clin Invest 34: Zantut-Wittmann DE, Ramos CD, Santos AO, Lima MM, Panzan AD, Facuri FV, Etchebehere EC, Lima MC, Tambascia MA, Camargo EE 2005 High pre-therapy [99mTc]pertechnetate thyroid uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131I]iodide therapy in Graves disease. Nucl Med Commun 26: Wilson R, Chopra M, Bradley H, McKillop JH, Smith WE, Thomson JA 1989 Free radicals and Graves disease: the effects of therapy. Clin Endocrinol (Oxf) 30: Isman CA, Yegen BC, Alican I 2003 Methimazole-induced hypothyroidism in rats ameliorates oxidative injury in experimental colitis. J Endocrinol 177: Imamura M, Aoki N, Saito T, Ohno Y, Maruyama Y, Yamaguchi J, Yamamoto T 1986 Inhibitory effects of antithyroid drugs on oxygen radical formation in human neutrophils. Acta Endocrinol (Copenh) 112: Wilson R, Buchanan L, Fraser WD, Jenkins C, Smith WE, Reglinski J, Thomson JA, McKillop JH 1998 Evidence for carbimazole as an antioxidant? Autoimmunity 27: Mitsiades N, Poulaki V, Tseleni-Balafouta S, Chrousos GP, Koutras DA 2000 Fas ligand expression in thyroid follicular cells from patients with thionamidetreated Graves disease. Thyroid 10: JCEM is published monthly by The Endocrine Society ( the foremost professional society serving the endocrine community.