Recombinant Human Thyrotropin Markedly Changes the 131I Kinetics during 131I Therapy of Patients with Nodular Goiter: An Evaluation by a Ran
http://www.100md.com
《临床内分泌与代谢杂志》
Abstract
The present study compares, in a randomized double-blinded design, the expected and the actual absorbed thyroid radioactive dose in response to 0.3 mg recombinant human (rh)TSH (n = 35) or placebo (n = 28) given 24 h before 131I therapy in patients with nodular goiter (median volume, 69 ml; range, 20–440 ml). The 131I activity calculation was based on thyroid 131I uptake (RAIU) at 24 and 96 h after a tracer dose of 0.5 MBq 131I. After 131I therapy, 24- and 96-h RAIU were repeated allowing a more exact assessment of the actual absorbed thyroid dose. The median 131I activity was 617 and 632 MBq, respectively, in the rhTSH and the placebo group. At baseline, the 24- and 96-h RAIU and the expected thyroid dose were 32.8 ± 9.1%, 32.1 ± 8.2%, and 96.3 ± 16.3 Gy, respectively, in the rhTSH group and 35.7 ± 11.8%, 35.2 ± 11.3%, and 94.1 ± 18.5 Gy, respectively, in the placebo group (P value not significant between groups). After 131I therapy, the 24- and 96-h RAIU and the actual absorbed thyroid dose were 46.9 ± 11.7%, 45.0 ± 12.1%, and 136.7 ± 47.9 Gy, respectively, in the rhTSH group and 33.0 ± 11.4%, 31.0 ± 11.3%, and 76.9 ± 27.5 Gy, respectively, in the placebo group (P < 0.001 between groups). Comparing the expected with the actual absorbed thyroid dose, this corresponds to a mean increase of 36.4% (95% confidence interval, 21.3–53.4) in the rhTSH group and a decrease of 21.5% (95% confidence interval, –33.9 to –6.6) in the placebo group (P < 0.001), equivalent to an increase of 73.8% in the absorbed thyroid dose in the rhTSH-treated group. We have thus for the first time shown that stimulation with rhTSH before 131I therapy not only hinders the decrease in the thyroid RAIU observed with conventional 131I therapy but in fact also significantly enhances the absorbed thyroid dose. Whether this also leads to a significant increase in goiter size reduction needs additional study.
Introduction
DURING THE LAST two decades radioiodine (131I) therapy has, in some countries, become the cornerstone in the treatment of patients with benign nontoxic nodular goiter (1). In other countries, patients are primarily referred to surgery or offered L-thyroxine treatment (1, 2), although the effect of the latter is questionable (3). In patients with nodular goiter, 131I therapy results in a mean thyroid volume reduction ranging from 40–60% within 1–2 yr after treatment (4, 5, 6).
The observed reluctance for using 131I in most countries may rely on several factors. In areas with high dietary iodine intake, the thyroid radioiodine uptake (RAIU) is low, resulting in the need of a relatively high amount of thyroid radioactivity, which often hinders out-patient treatment. Individual susceptibility to 131I, an inaccurately estimated thyroid size and dose calculation because of the known irregular 131I uptake in nodular goiters, may also impede the treatment results. In Graves’ disease, the thyroid RAIU displays a considerable variation with time (7), and the iodine biokinetics are furthermore affected by the goiter reduction itself (8). Whether these factors also play a role in case of nodular goiter is unknown but may potentially lead to an imprecise applied thyroid dose and hinder assessment of a possible dose-response relationship.
With the recent advent of recombinant human (rh)TSH, which has been shown to approximately double the 24-h thyroid RAIU (9, 10, 11) and also seems to cause a more homogeneous distribution of 131I on thyroid scintigrams of nodular goiters (12), the possibility of increasing the absorbed radioactive dose in the thyroid gland appears promising in dealing with the limited effect of 131I therapy. In studies not using rhTSH, an association seems to exist between the calculated thyroid dose and the obtained goiter reduction (5, 13). Little is known regarding exact dosimetry after rhTSH-augmented 131I therapy (14).
The aim of the present study was to investigate, in a randomized double-blinded placebo-controlled trial, the possible changes in the expected and the actual absorbed thyroid dose during rhTSH-augmented 131I therapy.
Subjects and Methods
Subjects and study design
The patient cohort consisted of a total of 63 patients (10 men, 53 women) with nontoxic and toxic nodular goiter and a median age of 55 yr (range, 31–87 yr). They were treated with 131I during the period from January 2001 to December 2003. Of these, 27 (43%) were euthyroid, 31 (49%) were subclinically hyperthyroid (serum-TSH < 0.30 mU/liter and normal serum-free-T4 index and serum-free-T3 index), and five (8%) were overtly hyperthyroid.
Treatment indications were symptoms from a compressive nodular goiter and/or cosmetic discomfort or hyperthyroidism. One patient had previously undergone 131I therapy, and nine patients had had a hemithyroidectomy. None had received iodine-containing agents or medication known to affect thyroid function or thyroid RAIU 3 months before therapy. An exception was the patients with overt hyperthyroidism who were kept euthyroid with antithyroid drugs (methimazole or propylthiouracil), which were discontinued 5 d before 131I therapy, with no resumption after therapy. None had clinical suspicion of thyroid malignancy. Thyroid 99mTc scintigraphy was performed before enrollment, and in case of dominant hypoactive nodules, fine-needle aspiration biopsy was performed to exclude malignancy.
Pregnancy was ruled out in all female patients of childbearing age by a urinary test immediately before therapy. Other exclusion criteria were breastfeeding, age less than 18 yr, and known ischemic heart disease (because of concern of transient thyrotoxicosis after rhTSH stimulation). Also patients with a 24-h thyroid RAIU less than 20% were excluded because we found it of concern to treat such patients in case they were randomized to the placebo group.
The study was performed in a randomized placebo-controlled double-blinded set-up in which each patient was randomized to receive either 0.3 mg rhTSH or isotonic saline injected im in the gluteal region 24 h before 131I therapy. Freeze-dried rhTSH (vials containing 0.9 mg rhTSH) (Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) was reconstituted with 3 ml isotonic saline. Of this dilution, 0.3 mg rhTSH corresponds to 1 ml. Randomization was performed by an independent pharmacist at the hospital. The study was approved by the local ethics committee of the county of Funen, Denmark (journal no. 20030128), and all patients provided signed informed consent before inclusion in the study.
Thyroid size
To reduce inaccuracy in thyroid size determination, patients were subdivided into group A with goiter size less than 100 ml (n = 42; median volume, 52 ml; range, 20–99 ml), and group B with goiter size more than or equal to 100 ml (n = 21; median volume, 183 ml; range, 100–440 ml). In the latter group, surgery would normally be the treatment of choice, but this was not feasible because of concomitant medical disorders, previous neck surgery, and/or patient preference.
Overall, the median goiter volume at baseline was 69 ml (range, 20–440 ml). Because of previous hemithyroidectomy, two patients had a goiter size of 20 ml and 24 ml, respectively. Thyroid size in group A was measured, as previously described (15), by a precise and accurate planimetric ultrasonic scanning procedure, using a 5.5-MHz compound scanner (type 1846; Brüel & Kj?r, Copenhagen, Denmark). The average intraobserver variation of this method is approximately 5% (15). In case the initial ultrasound examination showed a thyroid volume above 100 ml, the patient was allocated to group B. In this group, magnetic resonance imaging (MRI) was performed on a superconducting system (Gyroscan T5II, Phillips, Eindhoven, The Netherlands) operating at 0.5 Tesla. The procedure has previously been described in detail (16). The precision of thyroid volume estimates by MRI planimetry is high with an intraobserver coefficient of variation of 3.6% (16). Ultrasound and MRI measurements were performed by a single operator blinded toward the randomization.
Uptake measurements and 131I therapy
Calculation of the intended (i.e. expected) thyroid dose was based on the thyroid RAIU determined at 24 and 96 h after oral administration of a tracer activity of 0.5 MBq 131I (0.01 mCi). After 131I therapy, 24- and 96-h RAIU measurements were repeated, allowing an estimation of the actual absorbed thyroid dose.
Before administration, both tracer and therapy 131I 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-in NaI (TI)-scintillation probe (Atom-Lab 950, Biodex Medical Systems, New York, NY), with dead-time correction. When measuring uptake after therapy, the detector head was covered with an adjustable lead septum. The energy window was 364 KeV ± 15%, and the energy solution was controlled and corrected daily with a 137Cs test source. All measurements were background corrected.
131I therapy was given as a single oral dose, 10–14 d after the last tracer thyroid RAIU measurement. Aiming at an intended thyroid dose of 100 Gy, the administered therapeutic 131I activity was calculated based on the following algorithm: activity (MBq) = thyroid volume (ml) x 22.4 (d·MBq/ml) x 100/[T1/2 (d) x 24 h 131I uptake (%)].
Thyroid volume (i.e. weight) was estimated by ultrasound (group A) and MRI (group B), respectively. The effective half-life (T1/2) was calculated from the 24- and 96-h thyroid RAIU measurements.
According to the official radiation regulations, group A patients were treated on an out-patient basis receiving a maximum of 600 MBq 131I, and group B patients were hospitalized in isolation, receiving a maximum activity of 3700 MBq 131I. In seven (15.6%) of the out-patients (group A), the calculated thyroid 131I-activity was greater than 600 MBq because of a low thyroid RAIU. Because in-house therapy was not planned for these patients, they were given only 600 MBq (four patients received placebo and three patients received rhTSH). Similarly, in two (9.5%) of the in-house patients (group B), the calculated thyroid 131I activity was greater than 3700 MBq (both received rhTSH), but the administered 131I activity was restricted at this limit for practical reasons.
Statistical analysis
The STATA 8 statistical software program was used for data analysis. Nonparametric (Mann-Whitney) or parametric (Student’s t test) statistical tests were used, depending on the normality of the data. Calculation of the percent mean difference was based on log-transformed data, thereby making a decline of a variable equivalent to an increase. A simple linear regression was used to test for correlation. Data are presented as medians (range) or means (± SD). The level of statistical significance was chosen as a P value < 0.05.
Results
Thirty-five patients were randomized to the rhTSH group and 28 patients to the placebo group. The slight skewness in the randomization was caused by exclusion of three patients initially randomized to the placebo group, in whom the dosimetric measurements had to be cancelled because of equipment failure.
Patient characteristics are shown in Table 1. No significant differences were found between the rhTSH group and the placebo group in any of the baseline variables.
131I kinetics
At baseline, the tracer 24- and 96-h thyroid RAIU measurements were 32.8 ± 9.1 and 32.1 ± 8.2%, respectively, in the rhTSH group and 35.7 ±11.8 and 35.2 ± 11.3%, respectively, in the placebo group (P = 0.28 and P = 0.21, respectively, between groups), as shown in Fig. 1. In the rhTSH-treated group, the median 131I activity was 617 MBq (16.7 mCi; range, 241-3700 MBq) and in the placebo group it was 632 MBq (17.1 mCi; range, 180-3198 MBq), with no significant difference between the groups (P = 0.81) (Table 1). After 131I therapy, the 24- and 96-h thyroid RAIU increased in the rhTSH group to 46.9 ± 11.7 and 45.0 ± 12.1%, respectively, and decreased in the placebo group to 33.0 ± 11.4 and 31.0 ± 11.3%, respectively (P < 0.001 between groups at both times).
The mean effective half-life at baseline was 6.88 ± 1.26 and 7.05 ± 1.32 d in the rhTSH and placebo group, respectively (P = 0.60). In the rhTSH group, there was a slight but insignificant decrease to 6.58 ± 1.45 d (P = 0.39 compared with baseline) in this variable after therapy, whereas the decrease to 6.22 ± 1.90 d in the placebo group was more pronounced (P = 0.04 compared with baseline; P = 0.40 compared with the rhTSH group).
In the rhTSH-treated group, the actual absorbed thyroid dose increased significantly compared with the baseline calculations (Table 1 and Fig. 2), whereas the kinetics changed oppositely in the placebo group. Thus, in the rhTSH group the expected thyroid dose was 96.3 ± 16.3 Gy and increased to an actual absorbed dose of 136.7 ± 47.9 Gy (P < 0.001). The corresponding figures in the placebo group were 94.1 ± 18.5 and 76.9 ± 27.5 Gy, respectively (P = 0.007). The individual mean reduction in the thyroid dose (expected vs. actual absorbed) was 21.5% (95% confidence interval, –33.9 to –6.6%) in the placebo group, contrasting with an increase of 36.4% (95% confidence interval, 21.3–53.4%) in the rhTSH group (Table 1 and Fig. 2). This corresponds to an overall increase of 73.8% in the rhTSH-treated group compared with conventional therapy.
In the rhTSH-treated group, there were insignificant negative correlations between the baseline 24-h (r = –0.22; P = 0.21) and the 96-h (r = –0.31; P = 0.07) thyroid RAIU values and the relative increase in the absorbed dose (i.e. ratio of actual absorbed/expected).
Because it cannot be excluded that the withdrawal of the antithyroid drugs before 131I therapy in the five hyperthyroid patients may have affected the biokinetics, we reanalyzed our data omitting these individuals. However, this did not significantly affect the overall results (data not shown).
Discussion
In this double-blinded placebo-controlled trial comprising 63 patients, we investigated the effect of rhTSH on thyroid 131I kinetics during 131I therapy. The thyroid dose calculation was based both on a precise thyroid size estimation and assessment of the effective 131I half-life. We found that the actual absorbed thyroid dose increased approximately 36% after stimulation with rhTSH, whereas it decreased 22% without rhTSH, corresponding to an overall increase in the absorbed thyroid dose of 74% in the rhTSH-treated group. Thus, we have shown, for the first time, that stimulation with rhTSH before 131I therapy not only hinders the observed decrease in the thyroid RAIU after conventional 131I therapy but in fact also significantly enhances the absorbed thyroid dose.
We found a change of the 131I kinetics during conventional 131I therapy (placebo group), resulting in a thyroid dose significantly less than 100 Gy. The factors responsible for this phenomenon are not yet identified but may be caused by 131I release from the thyroid gland during therapy. In nine of our patients, the 131I activity was restricted. Consequently, the thyroid irradiation probably is lowered, which may affect the ensuing goiter reduction. However, this is unlikely to have any significant impact on the biokinetics. A factor also of importance when considering the accumulated thyroid 131I absorption is the effective 131I half-life. With the reservation that the calculation of the 131I half-life might have been more accurate by including more than two time points, this variable was not altered to any greater extent by the 131I therapy in the rhTSH-prestimulated group.
Theoretically, the increase in the absorbed thyroid dose with rhTSH prestimulation may amplify the goiter reduction after 131I therapy, which might be useful when dealing with large nodular goiters or goiters with low RAIU. In studies not using rhTSH (5, 13), the thyroid volume reduction seems to correlate positively with the thyroid dose. However, these results were based on post hoc analyses, and so far no controlled study has investigated whether a dose-response relationship exists regarding goiter reduction.
It has been shown that the effect of rhTSH on the 24-h RAIU in patients with nodular goiter is inversely correlated to the initial RAIU (10), suggesting that patients with a low thyroid RAIU in particular might benefit from rhTSH stimulation before 131I therapy. We found only a trend in that direction, probably because patients with a 24-h thyroid RAIU less than 20% were a priori excluded. This fact may also explain why Silva et al. (17) found a much higher effect on the RAIU (an increase from 18 to 46% after stimulation with 0.45 mg rhTSH), because the baseline 24-h RAIU of 33% in our patients clearly was higher.
Previous noncontrolled trials with rhTSH stimulation in healthy subjects or in patients with benign goiter have primarily focused on the 24-h thyroid RAIU (10, 11). Huysmans et al. (10) evaluated the changes in thyroid RAIU after rhTSH in 15 patients with nontoxic nodular goiter and found that the administration of 0.03 mg rhTSH 24 h before 131I increased the mean 24-h thyroid RAIU from 33 to 63%, thus an approximate doubling of the thyroid RAIU. Torres et al. (11) reported similar findings after giving six healthy euthyroid subjects 0.9 mg rhTSH. Despite using a much higher rhTSH dose, the obtainable thyroid RAIU was lower than what was seen in nodular goiters (10). This discrepancy is probably because of differences in iodine intake, but an influence of the difference in thyroid morphology and a wide interindividual variation in the thyroid RAIU response cannot be excluded. In the case of multinodular goiter, the thyroid RAIU undoubtedly is dependent on the general iodine load, extent of nodular autonomy, and the serum TSH level, the latter being of importance for the paranodular tissue. These factors also contribute to the inhomogeneous scintigrams typical for multinodular goiter.
In the context of 131I therapy, an altered biokinetics during the irradiation, in addition to factors earlier mentioned (7, 8), probably influences the absorbed thyroid dose. When treating patients with Graves’ disease, the absorbed thyroid dose may deviate significantly from what has been calculated based on initial tracer measurements (18). In addition, the applied thyroid dose may be strongly overestimated in nodular goiters if dose calculation is based only on 24-h thyroid RAIU and not the half-life (19). Certainly, important issues related to the 131I kinetics after rhTSH and 131I therapy need to be clarified. Nieuwlaat et al. (14) recently demonstrated that prestimulation (24 h before 131I administration) with either 0.01 or 0.03 mg rhTSH followed by a proportional reduction of the thyroid 131I activity to patients with nodular goiter resulted in a significantly lower irradiation of the extrathyroidal organs, while attaining a similar absorbed thyroid dose as patients receiving conventional 131I therapy. However, that study (14) was not a randomized trial, and it comprised only 18 patients. One year after therapy, the reduced 131I activity resulted in a mean thyroid volume reduction of 35% in the 0.01-mg rhTSH group and 41% in the 0.03-mg rhTSH group (20), results that are comparable with those found in previous studies not using rhTSH (3).
At present, only one study (17) has investigated whether rhTSH prestimulation is able to amplify the goiter reduction after 131I therapy. Silva et al. (17) investigated 34 patients with a very large multinodular goiter, randomized to 131I therapy alone or to 131I therapy preceded by 0.45 mg rhTSH to increase the thyroid dose. The 131I activity was calculated without taking the thyroid RAIU into account, thereby hindering a precise thyroid dose calculation. In the group receiving rhTSH, a mean goiter volume reduction of 57.8% at 12 months was seen, significantly higher than the 39.7% obtained in the control group. Thus, based on the present investigation, the higher thyroid volume reduction in the rhTSH-pretreated group can be explained by a higher retention of 131I in the thyroid. Whether the goiter reduction can be even further amplified by a higher dose of rhTSH and/or by increasing the 131I activity remains to be clarified (21).
Additional questions such as the optimum rhTSH dose, the optimum time interval between rhTSH stimulation and 131I therapy, and a possible effect by fractioning the rhTSH dose need to be addressed in future randomized studies. Finally, it should be taken into account that subjects stimulated with rhTSH, probably in a dose-dependent manner, are at risk of developing an acute thyroid gland enlargement and transient thyrotoxicosis (11, 22). Also local cervical pain (17) and permanent hypothyroidism (9, 17) seem much more frequent when 131I therapy is augmented by rhTSH.
Acknowledgments
We thank Peter B. Andersen, M.D. (Department of Radiology, Odense University Hospital), for performing the thyroid MRI and Lars Bastholt, M.D. (Department of Oncology, Odense University Hospital), for providing care for our in-patients.
Footnotes
This study was supported by research grants from The Agnes and Knut M?rk Foundation, Hans Skouby’s and Wife Emma Skouby’s Foundation, Jacob Madsen and Wife Olga Madsens’s Foundation, Dagmar Marshall’s Foundation, King Christian the X’s Foundation, Oda Pedersens Research Foundation, Frode V. Nyegaard and Wife’s Foundation, The Research Foundation of the County of Funen, The Novo Nordic Foundation, and The A. P. M?ller Relief Foundation.
First Published Online October 19, 2004
Abbreviations: MRI, Magnetic resonance imaging; RAIU, radioiodine uptake; rh, recombinant human.
Received August 4, 2004.
Accepted October 11, 2004.
References
Bonnema SJ, Bennedb?k FN, Wiersinga WM, Hegedüs L 2000 Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol (Oxf) 53:5–12
Bonnema SJ, Bennedb?k FN, Ladenson PW, Hegedüs L 2002 Management of the nontoxic multinodular goiter: a North American survey. J Clin Endocrinol Metab 87:112–117
Hegedüs L, Bonnema SJ, Bennedb?k FN 2003 Management of simple nodular goiter: current status and future perspectives. Endocr Rev 24:102–132
Hegedüs L, Hansen BM, Knudsen N, Hansen JM 1988 Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goiter. BMJ 297:661–662
Le Moli R, Wesche MF, Tiel-van Buul MM, Wiersinga WM 1999 Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goiter. Clin Endocrinol (Oxf) 50:783–789
Nygaard B, Hegedüs L, Gervil M, Hjalgrim H, Soe-Jensen P, Hansen JM 1993 Radioiodine treatment of multinodular non-toxic goitre. BMJ 307:828–832
Van Isselt JW, de Klerk JM, Koppeschaar HP, Van Rijk PP 2000 Iodine-131 uptake and turnover rate vary over short intervals in Graves’ disease. Nucl Med Commun 21:609–616
Traino AC, Di Martino F, Lazzeri M, Stabin MG 2000 Influence of thyroid volume reduction on calculated dose in radioiodine therapy of Graves’ hyperthyroidism. Phys Med Biol 45:121–129
Duick DS, Baskin HJ 2003 Utility of recombinant human thyrotropin for augmentation of radioiodine uptake and treatment of nontoxic and toxic multinodular goiters. Endocr Pract 9:204–209
Huysmans DA, Nieuwlaat WA, Erdtsieck RJ Schellekens AP, Bus JW, Bravenboer B, Hermus AR 2000 Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter. J Clin Endocrinol Metab 85:3592–3596
Torres MS, Ramirez L, Simkin PH, Braverman LE, Emerson CH 2001 Effect of various doses of recombinant human thyrotropin on the thyroid radioactive iodine uptake and serum levels of thyroid hormones and thyroglobulin in normal subjects. J Clin Endocrinol Metab 86:1660–1664
Nieuwlaat WA, Hermus AR, Sivro-Prndelj F, Corstens FH, Huysmans DA 2001 Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters. J Clin Endocrinol Metab 86:5330–5336
de Klerk JM, Van Isselt JW, van Dijk A, Hakman ME, Pameijer FA, Koppeschaar HPF, Zelissen PMJ, Van Schaik JPJ, Van Rijk PP 1997 Iodine-131 therapy in sporadic nontoxic goiter. J Nucl Med 38:372–376
Nieuwlaat WA, Hermus AR, Ross HA, Buijs WC, Edelbroek MA, Bus JW, Corstens FH, Huysmans DA 2004 Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone. J Nucl Med 45:626–633
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 relation to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 56:260–263
Bonnema SJ, Andersen PB, Knudsen DU, Hegedüs L 2002 MR imaging of large multinodular goiters: observer agreement on volume versus observer disagreement on dimensions of the involved trachea. AJR Am J Roentgenol 179:259–266
Silva MNC, Rubio IGS, Romao R, Gebrin EMMS, Buchpiguel C, Tomimori E, Camargo R, Cardia MS, Medeiros-Neto G 2003 Administration of a single dose of recombinant human thyrotropin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol (Oxf) 59:1–9
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 141:117–121
Berg GE, Michanek AM, Holmberg EC, Fink M 1996 Iodine-131 treatment of hyperthyroidism: significance of effective half-life measurements. J Nucl Med 37:228–232
Nieuwlaat WA, Huysmans DA, van den Bosch HC, Sweep CG, Ross HA, Corstens FH, Hermus AR 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:3121–3129
Nielsen VE, Bonnema SJ, Hegedüs L, The effects of recombinant human thyrotropin, in normal subjects and patients with goitre: a review. Clin Endocrinol (Oxf), in press
Nielsen VE, Bonnema SJ, Hegedüs L 2004 Effects of 0.9 mg recombinant human thyrotropin on thyroid size and function in normal subjects: a randomized, double-blind, cross-over trial. J Clin Endocrinol Metab 89:2242–2247(Viveque Egsgaard Nielsen,)
The present study compares, in a randomized double-blinded design, the expected and the actual absorbed thyroid radioactive dose in response to 0.3 mg recombinant human (rh)TSH (n = 35) or placebo (n = 28) given 24 h before 131I therapy in patients with nodular goiter (median volume, 69 ml; range, 20–440 ml). The 131I activity calculation was based on thyroid 131I uptake (RAIU) at 24 and 96 h after a tracer dose of 0.5 MBq 131I. After 131I therapy, 24- and 96-h RAIU were repeated allowing a more exact assessment of the actual absorbed thyroid dose. The median 131I activity was 617 and 632 MBq, respectively, in the rhTSH and the placebo group. At baseline, the 24- and 96-h RAIU and the expected thyroid dose were 32.8 ± 9.1%, 32.1 ± 8.2%, and 96.3 ± 16.3 Gy, respectively, in the rhTSH group and 35.7 ± 11.8%, 35.2 ± 11.3%, and 94.1 ± 18.5 Gy, respectively, in the placebo group (P value not significant between groups). After 131I therapy, the 24- and 96-h RAIU and the actual absorbed thyroid dose were 46.9 ± 11.7%, 45.0 ± 12.1%, and 136.7 ± 47.9 Gy, respectively, in the rhTSH group and 33.0 ± 11.4%, 31.0 ± 11.3%, and 76.9 ± 27.5 Gy, respectively, in the placebo group (P < 0.001 between groups). Comparing the expected with the actual absorbed thyroid dose, this corresponds to a mean increase of 36.4% (95% confidence interval, 21.3–53.4) in the rhTSH group and a decrease of 21.5% (95% confidence interval, –33.9 to –6.6) in the placebo group (P < 0.001), equivalent to an increase of 73.8% in the absorbed thyroid dose in the rhTSH-treated group. We have thus for the first time shown that stimulation with rhTSH before 131I therapy not only hinders the decrease in the thyroid RAIU observed with conventional 131I therapy but in fact also significantly enhances the absorbed thyroid dose. Whether this also leads to a significant increase in goiter size reduction needs additional study.
Introduction
DURING THE LAST two decades radioiodine (131I) therapy has, in some countries, become the cornerstone in the treatment of patients with benign nontoxic nodular goiter (1). In other countries, patients are primarily referred to surgery or offered L-thyroxine treatment (1, 2), although the effect of the latter is questionable (3). In patients with nodular goiter, 131I therapy results in a mean thyroid volume reduction ranging from 40–60% within 1–2 yr after treatment (4, 5, 6).
The observed reluctance for using 131I in most countries may rely on several factors. In areas with high dietary iodine intake, the thyroid radioiodine uptake (RAIU) is low, resulting in the need of a relatively high amount of thyroid radioactivity, which often hinders out-patient treatment. Individual susceptibility to 131I, an inaccurately estimated thyroid size and dose calculation because of the known irregular 131I uptake in nodular goiters, may also impede the treatment results. In Graves’ disease, the thyroid RAIU displays a considerable variation with time (7), and the iodine biokinetics are furthermore affected by the goiter reduction itself (8). Whether these factors also play a role in case of nodular goiter is unknown but may potentially lead to an imprecise applied thyroid dose and hinder assessment of a possible dose-response relationship.
With the recent advent of recombinant human (rh)TSH, which has been shown to approximately double the 24-h thyroid RAIU (9, 10, 11) and also seems to cause a more homogeneous distribution of 131I on thyroid scintigrams of nodular goiters (12), the possibility of increasing the absorbed radioactive dose in the thyroid gland appears promising in dealing with the limited effect of 131I therapy. In studies not using rhTSH, an association seems to exist between the calculated thyroid dose and the obtained goiter reduction (5, 13). Little is known regarding exact dosimetry after rhTSH-augmented 131I therapy (14).
The aim of the present study was to investigate, in a randomized double-blinded placebo-controlled trial, the possible changes in the expected and the actual absorbed thyroid dose during rhTSH-augmented 131I therapy.
Subjects and Methods
Subjects and study design
The patient cohort consisted of a total of 63 patients (10 men, 53 women) with nontoxic and toxic nodular goiter and a median age of 55 yr (range, 31–87 yr). They were treated with 131I during the period from January 2001 to December 2003. Of these, 27 (43%) were euthyroid, 31 (49%) were subclinically hyperthyroid (serum-TSH < 0.30 mU/liter and normal serum-free-T4 index and serum-free-T3 index), and five (8%) were overtly hyperthyroid.
Treatment indications were symptoms from a compressive nodular goiter and/or cosmetic discomfort or hyperthyroidism. One patient had previously undergone 131I therapy, and nine patients had had a hemithyroidectomy. None had received iodine-containing agents or medication known to affect thyroid function or thyroid RAIU 3 months before therapy. An exception was the patients with overt hyperthyroidism who were kept euthyroid with antithyroid drugs (methimazole or propylthiouracil), which were discontinued 5 d before 131I therapy, with no resumption after therapy. None had clinical suspicion of thyroid malignancy. Thyroid 99mTc scintigraphy was performed before enrollment, and in case of dominant hypoactive nodules, fine-needle aspiration biopsy was performed to exclude malignancy.
Pregnancy was ruled out in all female patients of childbearing age by a urinary test immediately before therapy. Other exclusion criteria were breastfeeding, age less than 18 yr, and known ischemic heart disease (because of concern of transient thyrotoxicosis after rhTSH stimulation). Also patients with a 24-h thyroid RAIU less than 20% were excluded because we found it of concern to treat such patients in case they were randomized to the placebo group.
The study was performed in a randomized placebo-controlled double-blinded set-up in which each patient was randomized to receive either 0.3 mg rhTSH or isotonic saline injected im in the gluteal region 24 h before 131I therapy. Freeze-dried rhTSH (vials containing 0.9 mg rhTSH) (Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) was reconstituted with 3 ml isotonic saline. Of this dilution, 0.3 mg rhTSH corresponds to 1 ml. Randomization was performed by an independent pharmacist at the hospital. The study was approved by the local ethics committee of the county of Funen, Denmark (journal no. 20030128), and all patients provided signed informed consent before inclusion in the study.
Thyroid size
To reduce inaccuracy in thyroid size determination, patients were subdivided into group A with goiter size less than 100 ml (n = 42; median volume, 52 ml; range, 20–99 ml), and group B with goiter size more than or equal to 100 ml (n = 21; median volume, 183 ml; range, 100–440 ml). In the latter group, surgery would normally be the treatment of choice, but this was not feasible because of concomitant medical disorders, previous neck surgery, and/or patient preference.
Overall, the median goiter volume at baseline was 69 ml (range, 20–440 ml). Because of previous hemithyroidectomy, two patients had a goiter size of 20 ml and 24 ml, respectively. Thyroid size in group A was measured, as previously described (15), by a precise and accurate planimetric ultrasonic scanning procedure, using a 5.5-MHz compound scanner (type 1846; Brüel & Kj?r, Copenhagen, Denmark). The average intraobserver variation of this method is approximately 5% (15). In case the initial ultrasound examination showed a thyroid volume above 100 ml, the patient was allocated to group B. In this group, magnetic resonance imaging (MRI) was performed on a superconducting system (Gyroscan T5II, Phillips, Eindhoven, The Netherlands) operating at 0.5 Tesla. The procedure has previously been described in detail (16). The precision of thyroid volume estimates by MRI planimetry is high with an intraobserver coefficient of variation of 3.6% (16). Ultrasound and MRI measurements were performed by a single operator blinded toward the randomization.
Uptake measurements and 131I therapy
Calculation of the intended (i.e. expected) thyroid dose was based on the thyroid RAIU determined at 24 and 96 h after oral administration of a tracer activity of 0.5 MBq 131I (0.01 mCi). After 131I therapy, 24- and 96-h RAIU measurements were repeated, allowing an estimation of the actual absorbed thyroid dose.
Before administration, both tracer and therapy 131I 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-in NaI (TI)-scintillation probe (Atom-Lab 950, Biodex Medical Systems, New York, NY), with dead-time correction. When measuring uptake after therapy, the detector head was covered with an adjustable lead septum. The energy window was 364 KeV ± 15%, and the energy solution was controlled and corrected daily with a 137Cs test source. All measurements were background corrected.
131I therapy was given as a single oral dose, 10–14 d after the last tracer thyroid RAIU measurement. Aiming at an intended thyroid dose of 100 Gy, the administered therapeutic 131I activity was calculated based on the following algorithm: activity (MBq) = thyroid volume (ml) x 22.4 (d·MBq/ml) x 100/[T1/2 (d) x 24 h 131I uptake (%)].
Thyroid volume (i.e. weight) was estimated by ultrasound (group A) and MRI (group B), respectively. The effective half-life (T1/2) was calculated from the 24- and 96-h thyroid RAIU measurements.
According to the official radiation regulations, group A patients were treated on an out-patient basis receiving a maximum of 600 MBq 131I, and group B patients were hospitalized in isolation, receiving a maximum activity of 3700 MBq 131I. In seven (15.6%) of the out-patients (group A), the calculated thyroid 131I-activity was greater than 600 MBq because of a low thyroid RAIU. Because in-house therapy was not planned for these patients, they were given only 600 MBq (four patients received placebo and three patients received rhTSH). Similarly, in two (9.5%) of the in-house patients (group B), the calculated thyroid 131I activity was greater than 3700 MBq (both received rhTSH), but the administered 131I activity was restricted at this limit for practical reasons.
Statistical analysis
The STATA 8 statistical software program was used for data analysis. Nonparametric (Mann-Whitney) or parametric (Student’s t test) statistical tests were used, depending on the normality of the data. Calculation of the percent mean difference was based on log-transformed data, thereby making a decline of a variable equivalent to an increase. A simple linear regression was used to test for correlation. Data are presented as medians (range) or means (± SD). The level of statistical significance was chosen as a P value < 0.05.
Results
Thirty-five patients were randomized to the rhTSH group and 28 patients to the placebo group. The slight skewness in the randomization was caused by exclusion of three patients initially randomized to the placebo group, in whom the dosimetric measurements had to be cancelled because of equipment failure.
Patient characteristics are shown in Table 1. No significant differences were found between the rhTSH group and the placebo group in any of the baseline variables.
131I kinetics
At baseline, the tracer 24- and 96-h thyroid RAIU measurements were 32.8 ± 9.1 and 32.1 ± 8.2%, respectively, in the rhTSH group and 35.7 ±11.8 and 35.2 ± 11.3%, respectively, in the placebo group (P = 0.28 and P = 0.21, respectively, between groups), as shown in Fig. 1. In the rhTSH-treated group, the median 131I activity was 617 MBq (16.7 mCi; range, 241-3700 MBq) and in the placebo group it was 632 MBq (17.1 mCi; range, 180-3198 MBq), with no significant difference between the groups (P = 0.81) (Table 1). After 131I therapy, the 24- and 96-h thyroid RAIU increased in the rhTSH group to 46.9 ± 11.7 and 45.0 ± 12.1%, respectively, and decreased in the placebo group to 33.0 ± 11.4 and 31.0 ± 11.3%, respectively (P < 0.001 between groups at both times).
The mean effective half-life at baseline was 6.88 ± 1.26 and 7.05 ± 1.32 d in the rhTSH and placebo group, respectively (P = 0.60). In the rhTSH group, there was a slight but insignificant decrease to 6.58 ± 1.45 d (P = 0.39 compared with baseline) in this variable after therapy, whereas the decrease to 6.22 ± 1.90 d in the placebo group was more pronounced (P = 0.04 compared with baseline; P = 0.40 compared with the rhTSH group).
In the rhTSH-treated group, the actual absorbed thyroid dose increased significantly compared with the baseline calculations (Table 1 and Fig. 2), whereas the kinetics changed oppositely in the placebo group. Thus, in the rhTSH group the expected thyroid dose was 96.3 ± 16.3 Gy and increased to an actual absorbed dose of 136.7 ± 47.9 Gy (P < 0.001). The corresponding figures in the placebo group were 94.1 ± 18.5 and 76.9 ± 27.5 Gy, respectively (P = 0.007). The individual mean reduction in the thyroid dose (expected vs. actual absorbed) was 21.5% (95% confidence interval, –33.9 to –6.6%) in the placebo group, contrasting with an increase of 36.4% (95% confidence interval, 21.3–53.4%) in the rhTSH group (Table 1 and Fig. 2). This corresponds to an overall increase of 73.8% in the rhTSH-treated group compared with conventional therapy.
In the rhTSH-treated group, there were insignificant negative correlations between the baseline 24-h (r = –0.22; P = 0.21) and the 96-h (r = –0.31; P = 0.07) thyroid RAIU values and the relative increase in the absorbed dose (i.e. ratio of actual absorbed/expected).
Because it cannot be excluded that the withdrawal of the antithyroid drugs before 131I therapy in the five hyperthyroid patients may have affected the biokinetics, we reanalyzed our data omitting these individuals. However, this did not significantly affect the overall results (data not shown).
Discussion
In this double-blinded placebo-controlled trial comprising 63 patients, we investigated the effect of rhTSH on thyroid 131I kinetics during 131I therapy. The thyroid dose calculation was based both on a precise thyroid size estimation and assessment of the effective 131I half-life. We found that the actual absorbed thyroid dose increased approximately 36% after stimulation with rhTSH, whereas it decreased 22% without rhTSH, corresponding to an overall increase in the absorbed thyroid dose of 74% in the rhTSH-treated group. Thus, we have shown, for the first time, that stimulation with rhTSH before 131I therapy not only hinders the observed decrease in the thyroid RAIU after conventional 131I therapy but in fact also significantly enhances the absorbed thyroid dose.
We found a change of the 131I kinetics during conventional 131I therapy (placebo group), resulting in a thyroid dose significantly less than 100 Gy. The factors responsible for this phenomenon are not yet identified but may be caused by 131I release from the thyroid gland during therapy. In nine of our patients, the 131I activity was restricted. Consequently, the thyroid irradiation probably is lowered, which may affect the ensuing goiter reduction. However, this is unlikely to have any significant impact on the biokinetics. A factor also of importance when considering the accumulated thyroid 131I absorption is the effective 131I half-life. With the reservation that the calculation of the 131I half-life might have been more accurate by including more than two time points, this variable was not altered to any greater extent by the 131I therapy in the rhTSH-prestimulated group.
Theoretically, the increase in the absorbed thyroid dose with rhTSH prestimulation may amplify the goiter reduction after 131I therapy, which might be useful when dealing with large nodular goiters or goiters with low RAIU. In studies not using rhTSH (5, 13), the thyroid volume reduction seems to correlate positively with the thyroid dose. However, these results were based on post hoc analyses, and so far no controlled study has investigated whether a dose-response relationship exists regarding goiter reduction.
It has been shown that the effect of rhTSH on the 24-h RAIU in patients with nodular goiter is inversely correlated to the initial RAIU (10), suggesting that patients with a low thyroid RAIU in particular might benefit from rhTSH stimulation before 131I therapy. We found only a trend in that direction, probably because patients with a 24-h thyroid RAIU less than 20% were a priori excluded. This fact may also explain why Silva et al. (17) found a much higher effect on the RAIU (an increase from 18 to 46% after stimulation with 0.45 mg rhTSH), because the baseline 24-h RAIU of 33% in our patients clearly was higher.
Previous noncontrolled trials with rhTSH stimulation in healthy subjects or in patients with benign goiter have primarily focused on the 24-h thyroid RAIU (10, 11). Huysmans et al. (10) evaluated the changes in thyroid RAIU after rhTSH in 15 patients with nontoxic nodular goiter and found that the administration of 0.03 mg rhTSH 24 h before 131I increased the mean 24-h thyroid RAIU from 33 to 63%, thus an approximate doubling of the thyroid RAIU. Torres et al. (11) reported similar findings after giving six healthy euthyroid subjects 0.9 mg rhTSH. Despite using a much higher rhTSH dose, the obtainable thyroid RAIU was lower than what was seen in nodular goiters (10). This discrepancy is probably because of differences in iodine intake, but an influence of the difference in thyroid morphology and a wide interindividual variation in the thyroid RAIU response cannot be excluded. In the case of multinodular goiter, the thyroid RAIU undoubtedly is dependent on the general iodine load, extent of nodular autonomy, and the serum TSH level, the latter being of importance for the paranodular tissue. These factors also contribute to the inhomogeneous scintigrams typical for multinodular goiter.
In the context of 131I therapy, an altered biokinetics during the irradiation, in addition to factors earlier mentioned (7, 8), probably influences the absorbed thyroid dose. When treating patients with Graves’ disease, the absorbed thyroid dose may deviate significantly from what has been calculated based on initial tracer measurements (18). In addition, the applied thyroid dose may be strongly overestimated in nodular goiters if dose calculation is based only on 24-h thyroid RAIU and not the half-life (19). Certainly, important issues related to the 131I kinetics after rhTSH and 131I therapy need to be clarified. Nieuwlaat et al. (14) recently demonstrated that prestimulation (24 h before 131I administration) with either 0.01 or 0.03 mg rhTSH followed by a proportional reduction of the thyroid 131I activity to patients with nodular goiter resulted in a significantly lower irradiation of the extrathyroidal organs, while attaining a similar absorbed thyroid dose as patients receiving conventional 131I therapy. However, that study (14) was not a randomized trial, and it comprised only 18 patients. One year after therapy, the reduced 131I activity resulted in a mean thyroid volume reduction of 35% in the 0.01-mg rhTSH group and 41% in the 0.03-mg rhTSH group (20), results that are comparable with those found in previous studies not using rhTSH (3).
At present, only one study (17) has investigated whether rhTSH prestimulation is able to amplify the goiter reduction after 131I therapy. Silva et al. (17) investigated 34 patients with a very large multinodular goiter, randomized to 131I therapy alone or to 131I therapy preceded by 0.45 mg rhTSH to increase the thyroid dose. The 131I activity was calculated without taking the thyroid RAIU into account, thereby hindering a precise thyroid dose calculation. In the group receiving rhTSH, a mean goiter volume reduction of 57.8% at 12 months was seen, significantly higher than the 39.7% obtained in the control group. Thus, based on the present investigation, the higher thyroid volume reduction in the rhTSH-pretreated group can be explained by a higher retention of 131I in the thyroid. Whether the goiter reduction can be even further amplified by a higher dose of rhTSH and/or by increasing the 131I activity remains to be clarified (21).
Additional questions such as the optimum rhTSH dose, the optimum time interval between rhTSH stimulation and 131I therapy, and a possible effect by fractioning the rhTSH dose need to be addressed in future randomized studies. Finally, it should be taken into account that subjects stimulated with rhTSH, probably in a dose-dependent manner, are at risk of developing an acute thyroid gland enlargement and transient thyrotoxicosis (11, 22). Also local cervical pain (17) and permanent hypothyroidism (9, 17) seem much more frequent when 131I therapy is augmented by rhTSH.
Acknowledgments
We thank Peter B. Andersen, M.D. (Department of Radiology, Odense University Hospital), for performing the thyroid MRI and Lars Bastholt, M.D. (Department of Oncology, Odense University Hospital), for providing care for our in-patients.
Footnotes
This study was supported by research grants from The Agnes and Knut M?rk Foundation, Hans Skouby’s and Wife Emma Skouby’s Foundation, Jacob Madsen and Wife Olga Madsens’s Foundation, Dagmar Marshall’s Foundation, King Christian the X’s Foundation, Oda Pedersens Research Foundation, Frode V. Nyegaard and Wife’s Foundation, The Research Foundation of the County of Funen, The Novo Nordic Foundation, and The A. P. M?ller Relief Foundation.
First Published Online October 19, 2004
Abbreviations: MRI, Magnetic resonance imaging; RAIU, radioiodine uptake; rh, recombinant human.
Received August 4, 2004.
Accepted October 11, 2004.
References
Bonnema SJ, Bennedb?k FN, Wiersinga WM, Hegedüs L 2000 Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol (Oxf) 53:5–12
Bonnema SJ, Bennedb?k FN, Ladenson PW, Hegedüs L 2002 Management of the nontoxic multinodular goiter: a North American survey. J Clin Endocrinol Metab 87:112–117
Hegedüs L, Bonnema SJ, Bennedb?k FN 2003 Management of simple nodular goiter: current status and future perspectives. Endocr Rev 24:102–132
Hegedüs L, Hansen BM, Knudsen N, Hansen JM 1988 Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goiter. BMJ 297:661–662
Le Moli R, Wesche MF, Tiel-van Buul MM, Wiersinga WM 1999 Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goiter. Clin Endocrinol (Oxf) 50:783–789
Nygaard B, Hegedüs L, Gervil M, Hjalgrim H, Soe-Jensen P, Hansen JM 1993 Radioiodine treatment of multinodular non-toxic goitre. BMJ 307:828–832
Van Isselt JW, de Klerk JM, Koppeschaar HP, Van Rijk PP 2000 Iodine-131 uptake and turnover rate vary over short intervals in Graves’ disease. Nucl Med Commun 21:609–616
Traino AC, Di Martino F, Lazzeri M, Stabin MG 2000 Influence of thyroid volume reduction on calculated dose in radioiodine therapy of Graves’ hyperthyroidism. Phys Med Biol 45:121–129
Duick DS, Baskin HJ 2003 Utility of recombinant human thyrotropin for augmentation of radioiodine uptake and treatment of nontoxic and toxic multinodular goiters. Endocr Pract 9:204–209
Huysmans DA, Nieuwlaat WA, Erdtsieck RJ Schellekens AP, Bus JW, Bravenboer B, Hermus AR 2000 Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter. J Clin Endocrinol Metab 85:3592–3596
Torres MS, Ramirez L, Simkin PH, Braverman LE, Emerson CH 2001 Effect of various doses of recombinant human thyrotropin on the thyroid radioactive iodine uptake and serum levels of thyroid hormones and thyroglobulin in normal subjects. J Clin Endocrinol Metab 86:1660–1664
Nieuwlaat WA, Hermus AR, Sivro-Prndelj F, Corstens FH, Huysmans DA 2001 Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters. J Clin Endocrinol Metab 86:5330–5336
de Klerk JM, Van Isselt JW, van Dijk A, Hakman ME, Pameijer FA, Koppeschaar HPF, Zelissen PMJ, Van Schaik JPJ, Van Rijk PP 1997 Iodine-131 therapy in sporadic nontoxic goiter. J Nucl Med 38:372–376
Nieuwlaat WA, Hermus AR, Ross HA, Buijs WC, Edelbroek MA, Bus JW, Corstens FH, Huysmans DA 2004 Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone. J Nucl Med 45:626–633
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 relation to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 56:260–263
Bonnema SJ, Andersen PB, Knudsen DU, Hegedüs L 2002 MR imaging of large multinodular goiters: observer agreement on volume versus observer disagreement on dimensions of the involved trachea. AJR Am J Roentgenol 179:259–266
Silva MNC, Rubio IGS, Romao R, Gebrin EMMS, Buchpiguel C, Tomimori E, Camargo R, Cardia MS, Medeiros-Neto G 2003 Administration of a single dose of recombinant human thyrotropin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol (Oxf) 59:1–9
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 141:117–121
Berg GE, Michanek AM, Holmberg EC, Fink M 1996 Iodine-131 treatment of hyperthyroidism: significance of effective half-life measurements. J Nucl Med 37:228–232
Nieuwlaat WA, Huysmans DA, van den Bosch HC, Sweep CG, Ross HA, Corstens FH, Hermus AR 2003 Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 88:3121–3129
Nielsen VE, Bonnema SJ, Hegedüs L, The effects of recombinant human thyrotropin, in normal subjects and patients with goitre: a review. Clin Endocrinol (Oxf), in press
Nielsen VE, Bonnema SJ, Hegedüs L 2004 Effects of 0.9 mg recombinant human thyrotropin on thyroid size and function in normal subjects: a randomized, double-blind, cross-over trial. J Clin Endocrinol Metab 89:2242–2247(Viveque Egsgaard Nielsen,)