THERAPY OF ENDOCRINE DISEASE: Recombinant human TSH and radioactive iodine therapy in the management of benign multinodular goiter

in European Journal of Endocrinology
Author: Hans Graf1
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  • 1 Endocrine and Metabolic Unit of the Federal University of Paraná, Rua Solimões, 1184, Mercês, Curitiba, Paraná, Brazil

Correspondence should be addressed to H Graf; Email: hansgraf@bighost.com.br
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Multinodular goiter (MNG) is a very common thyroid disorder determined by diverse goitrogenic factors, the most important one being iodine deficiency. The clinical presentation of a patient with MNG varies from a completely asymptomatic goiter to a life-threatening disease due to upper airway compression. Patients can develop underlying subclinical or overt hyperthyroidism due to autonomously hyperfunctioning nodules. In the absence of clinical, ultrasonographic, or cytological findings suggestive of malignancy, the best therapeutic approach for a patient with MNG will depend on the size and location of the goiter, the presence and severity of compressive symptoms, and the presence or absence of thyrotoxicosis. There is still no consensus regarding the treatment of atoxic MNGs. Hence, its optimal management remains controversial; possible therapies include levothyroxine (lT4), surgery, and radioactive iodine (131I). Suppressive treatment with lT4 is discouraged due to the development of sub-clinical or overt hyperthyroidism and to its low efficacy when compared with surgery or 131I. Total thyroidectomy is effective; however, it is associated with the risk of surgical complications and is often refused by the patient. 131I therapy is an alternative to thyroid surgery to reduce the size of benign MNGs. Based on the ability of recombinant human TSH (rhTSH) to more than double thyroid 131I uptake, this compound has been evaluated as an adjuvant to 131I in the treatment of MNG. Very small doses of rhTSH have been used in patients with MNG and few safety concerns have been observed, but the ideal dose, both effective and safe, is yet to be defined.

Abstract

Multinodular goiter (MNG) is a very common thyroid disorder determined by diverse goitrogenic factors, the most important one being iodine deficiency. The clinical presentation of a patient with MNG varies from a completely asymptomatic goiter to a life-threatening disease due to upper airway compression. Patients can develop underlying subclinical or overt hyperthyroidism due to autonomously hyperfunctioning nodules. In the absence of clinical, ultrasonographic, or cytological findings suggestive of malignancy, the best therapeutic approach for a patient with MNG will depend on the size and location of the goiter, the presence and severity of compressive symptoms, and the presence or absence of thyrotoxicosis. There is still no consensus regarding the treatment of atoxic MNGs. Hence, its optimal management remains controversial; possible therapies include levothyroxine (lT4), surgery, and radioactive iodine (131I). Suppressive treatment with lT4 is discouraged due to the development of sub-clinical or overt hyperthyroidism and to its low efficacy when compared with surgery or 131I. Total thyroidectomy is effective; however, it is associated with the risk of surgical complications and is often refused by the patient. 131I therapy is an alternative to thyroid surgery to reduce the size of benign MNGs. Based on the ability of recombinant human TSH (rhTSH) to more than double thyroid 131I uptake, this compound has been evaluated as an adjuvant to 131I in the treatment of MNG. Very small doses of rhTSH have been used in patients with MNG and few safety concerns have been observed, but the ideal dose, both effective and safe, is yet to be defined.

Introduction

Radioactive iodine (131I) was introduced almost three decades ago for the treatment of multinodular goiter (MNG) (1). Since then, studies have demonstrated that 131I is safe and effective (2, 3), leading to significant thyroid volume (TV) reduction, when compared with levothyroxine (lT4) suppressive therapy. Overall, lT4 suppressive therapy offers no benefit (4), particularly regarding the improvement in obstructive symptoms (such as dyspnea and dysphagia), to most patients (5, 6). 131I treatment reduces the MNG volume by ∼40% after 1 year and by 50–60% after 2–5 years (4, 5, 6, 7, 8, 9). Nonetheless, the therapeutic efficacy of 131I in patients with MNG depends to some extent on the 131I uptake (RAIU). Frequently, MNGs have a low and heterogeneous RAIU, requiring high 131I activities (10).

The administration of recombinant human thyrotropin (rhTSH) before 131I has been shown to be a potentially valuable therapeutic tool for the management of MNG (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). rhTSH in a low single dose increases 131I uptake by two- to fourfold, and homogenizes RAIU (21, 22). The effect of rhTSH on RAIU allows for the administration of lower 131I activities, with similar therapeutic effects (in comparison with higher 131I activities without rhTSH prestimulation), and with lower exposure of extrathyroidal tissues to radiation (23). When usual 131I activities are administered after rhTSH, greater TV reduction has been observed; 33–62% TV reduction when rhTSH plus 131I are administered, compared with 13–46% when placebo and the same 131I activities are given (11, 14, 16, 19, 24, 25). Overall, it has been shown that rhTSH doses lower than 0.1 mg do not cause acute increases in TV or thyroid hormone levels (26). When given 24 h before the administration of fixed or calculated 131I activities, rhTSH is a safe and efficacious adjunct therapeutic approach that allows for the administration of lower 131I activities (24).

Approach to the patient with MNG

Surgery

MNG is defined as the enlargement of the thyroid gland, in the absence of autoimmune thyroid disease, malignancy, or inflammation, and associated with more than one nodule identified clinically, ultrasonographically, or surgically. Factors that favor surgery as the treatment of choice include presence of symptoms or signs of compression within the neck, concern for co-existing thyroid cancer, substernal or retrosternal extension, or need for rapid correction of the thyrotoxic state (27). Factors weighing against the choice of surgery include significant comorbidity such as cardiopulmonar disease, or other debilitating disorders. In other cases, the patient or patient's family refuse surgery.

Radioactive iodine

For more than seven decades, 131I therapy has been used to treat thyroid diseases, mainly Graves’ disease. 131I not only is effective for curing hyperthyroid states, but also leads to shrinkage of the thyroid gland. Owing to the effect on the gland volume, 131I has been used in the treatment of compressive nontoxic nodular goiters. In 1988, Hegedus et al. (1), using ultrasonography, demonstrated that 131I treatment of nontoxic MNG leads to significant goiter volume reduction after 1 year. A number of studies, using ultrasonography, computed tomography, or magnetic resonance imaging, for accurate measurements of TV have shown that 131I therapy in patients with nontoxic nodular goiter results in a mean reduction in the TV by ∼40% after 1 year (1, 2, 6), and by 50–60% after 3–5 years (2, 4, 5, 6, 7, 8, 9, 28), with improvement in obstructive symptoms in the majority of patients (5, 6). The improvement in compressive symptoms is accompanied by significant tracheal widening, as measured by magnetic resonance imaging (6), and improvement in respiratory function (29). The amount of 131I administered depends on thyroid weight and RAIU. Administered doses are ∼100 mCi (3.7 MBq) 131I/g thyroid tissue corrected for RAIU at 24 h (28). As patients with nontoxic nodular goiter usually have a rather low and heterogeneous RAIU, they require high doses of 131I activities (10), causing considerable irradiation of extrathyroidal organs and tissues (30), requiring hospitalization and isolation (28) in most cases. Therefore, there was interest to explore strategies to enhance RAIU in these patients.

Recombinant human thyrotropin

The administration of a single, low dose of rhTSH considerably increased RAIU in patients with nodular goiter (21). A dose of 0.01 mg rhTSH given 24 h before 131I increased 24-h RAIU from 29 to 51%, while 0.03 mg rhTSH increased 24-h RAIU from 33 to 63% (21). A single, low dose of rhTSH not only doubled 24-h RAIU, but also determined a more homogeneous distribution of 131I within the thyroid gland in patients with nodular goiter, by stimulating 131I uptake in relatively cold areas, more than in relatively hot areas (22). It has been shown that pretreatment with a single, low dose of rhTSH allows for dose reduction of 131I in patients with nodular goiter (31). 131I therapy after pretreatment with a single, low dose of rhTSH in patients with nodular goiter resulted in TV reduction 1 year after therapy by 35% in the group pretreated with 0.01 mg rhTSH, and by 41% in the group pretreated with 0.03 mg rhTSH. This was accompanied by an increase in the smallest cross-sectional area of the tracheal lumen, by 17 and 44% respectively (31).

rhTSH and 131I for MNG

In patients with toxic MNG (TMNG), medical management before 131I therapy should be tailored based on the severity of the hyperthyroidism, patient's age, and comorbid conditions. Worsening of hyperthyroidism with increased heart rate, and rare cases of supraventricular tachycardia (including atrial fibrillation) have been observed in patients with TMNG or MNG treated with 131I (32, 33). Therefore, the use of β-blockers to prevent post-treatment tachyarrhythmias should be considered in all patients with TMNG who are older than 60 years of age and those with cardiovascular disease or severe hyperthyroidism (34). Pretreatment with methimazole before 131I therapy for TMNG is indicated in patients who are at an increased risk for complications due to worsening of hyperthyroidism, including elderly and those with cardiovascular disease or severe hyperthyroidism (35). rhTSH can at least double thyroid RAIU (12, 18, 36, 37, 38), depending on the baseline RAIU, and it determines a more homogeneous distribution of 131I in MNG (22). During the last decade, and based on the above observations, rhTSH has been evaluated as an adjuvant to 131I therapy, in an attempt to improve the efficacy of this treatment for MNG (18, 39, 40). Different rhTSH doses have been utilized: in some studies 0.2 mg or more (41, 42, 43, 44, 45, 46, 47), while in others 0.1 mg or less (11, 16, 20, 24, 31, 48). Since the introduction of rhTSH as an aid for 131I therapy in MNG, nine randomized controlled trials (RCTs) have been published (11, 14, 15, 16, 19, 24, 25, 44, 45). Despite variations in population characteristics, sample sizes, different rhTSH agents and dosages, radiotherapy methods, outcome analyses, and methodological biases, all RCTs have shown the superiority of rhTSH before 131I therapy over 131I alone to reduce the goiter volume.

Our personal experience with rhTSH and 131I

Following the demonstration that rhTSH was an excellent adjunct therapeutic approach for patients undergoing MNG treatment that allowed for the administration of lower 131I activities (21), we began to use it in different dosages, looking for the safest and still efficacious dose. Our first study employed two consecutive doses of 0.1 mg rhTSH before 131I (12). Owing to the heterogeneity of goiter size and the fact that we used a fixed 131I activity (30 mCi; 1.11 MBq), we calculated the retained thyroid 131I activity and determined correlations with the volume reduction of the goiter. We were able to show a positive correlation between the radiation dose to the thyroid and the decrease in TV at 6 months (Fig. 1) (12). Approximately one-third of our patients receiving 0.2 mg rhTSH developed mild thyrotoxic symptoms controlled easily by the administration of a β-blocking agent (12). In an attempt to lessen the adverse effects, the second study employed a single dose of 0.1 mg rhTSH (20). All patients with low and heterogeneous RAIU developed increased and homogeneous RAIU (Fig. 2) (49). TV was significantly reduced by 46.0±14.6% after 1 year; after 2 years, TV reduction was sustained in most patients (50). A typical example of goiter shrinkage is shown in Fig. 3 (49). After rhTSH administration, RAIU significantly increased from 18.1±9.7 to 49.6±13.4%. The ratio between post- and pre-rhTSH RAIU (RR) was calculated to indicate the fold increase in uptake in response to rhTSH. The median RR was 2.6 (1.2–9.2). There was an inverse correlation between RR and the pre-rhTSH 131I 24-h uptake (r=−0.613, P=0.009), indicating that patients with lower basal uptake values achieved higher RR values. Fast et al. (51) also demonstrated in a multicentric study that patients with baseline RAIU <20% achieved a greater reduction in the goiter size using modified-release rhTSH (MRrhTSH, an analog to rhTSH that is equipotent for increasing thyroid RAIU and that determines a lower peak plasma TSH concentration). MRrhTSH has an altered PK with a later Tmax than aqueous rhTSH. Potentially, MRrhTSH could reduce the side effects due to altered pharmacokinetics, with a delayed time to reach the maximum TSH concentration when compared with aqueous rhTSH (19). Our third study compared two different rhTSH doses (0.005 and 0.1 mg) with one placebo group (16) followed by a fixed 30 mCi (1.11 GBq) activity. We demonstrated that a very low dose of 0.005 mg rhTSH was equally safe and effective as 0.1 mg rhTSH. Both doses increased the efficacy of 131I (12). In a multicentric RCT, we compared two different MRrhTSH doses (0.01 and 0.03 mg) vs placebo (19). The study showed that the threshold for efficacy seems to be ∼0.03 mg rhTSH, at which dose there are only few minor safety concerns (19).

Figure 1
Figure 1

Significant positive correlation between the degree of goiter volume reduction and the effective uCi/g activity of administered 131I (r=0.676, P=0.002).

Citation: European Journal of Endocrinology 172, 2; 10.1530/EJE-14-0608

Figure 2
Figure 2

Scintigraphy before (A) and 24 h after the administration of 0.1 mg rhTSH in a single dose (B). Besides making the uptake of 131I more homogeneous, rhTSH increased the 24-h uptake from 4.5 to 39.3%.

Citation: European Journal of Endocrinology 172, 2; 10.1530/EJE-14-0608

Figure 3
Figure 3

An example of goiter reduction. Computerized tomography with multiplanar reconstruction of a patient with multinodular substernal goiter treated with 30 mCi (1.11 MBq) radioactive iodine after 0.1 mg rhTSH. (A1) and (A2): baseline (thyroid volume 147 ml); (B1) and (B2): 1 year after treatment (thyroid volume 42 ml).

Citation: European Journal of Endocrinology 172, 2; 10.1530/EJE-14-0608

Side effects of rhTSH use in MNG

Sensation of thyroidal swelling can occur, but no acute compressive effects have been observed with 0.3 mg rhTSH (45). In a selected group of patients with asymptomatic goiter (median volume of 40.0 ml), a 24% transient goiter volume increase was reported to occur 24 h after the administration of 0.3 mg rhTSH (45). Adjunct therapies with very small doses of rhTSH (0.01–0.03 mg) have been evaluated in both euthyroid and hyperthyroid patients with MNG, and few safety concerns have been observed (19, 20). However, one study showed that hyperthyroid patients had higher increases in thyroid hormone levels after 0.1 mg rhTSH plus 131I, with a higher frequency of side effects (46). Currently, the rhTSH adjunct therapy is not indicated in patients with TMNG (52). In patients with critical tracheal narrowing, prophylactic glucocorticoid therapy should be considered to prevent rhTSH and 131I-related swelling and further respiratory compromise (52). Painful transient thyroiditis may occur within the first month after treatment. Development of Graves’ hyperthyroidism (with high levels of TSH receptor antibodies) in patients with preexisting high thyroid peroxidase antibody concentrations has also been described after treatment of euthyroid MNG with RAI (35). Hypothyroidism development is common and depends on the size of the treated goiter and the administered rhTSH dose and 131I activity (11, 14, 15, 16, 24, 25, 44, 45, 49). It is important to mention that the adjunct therapy of MNG with rhTSH and 131I is not approved by the FDA or EMEA. Moreover, the cost-effectiveness of combined rhTSH has not been demonstrated. As an alternative to rhTSH, two studies showed that, in patients with MNG, methimazole-induced hypothyroidism increases endogenous TSH levels, augmenting RAIU and allowing for the administration of more effective activities of 131I (53, 54). Until now, no studies have compared the efficiency and safety of exogenous TSH vs endogenous TSH.

Concluding remarks

In patients with MNG, 131I therapy preceded by rhTSH further enhances goiter volume shrinkage, compared with 131I treatment alone. This effect has been demonstrated in short- and long-term studies, but it is still unknown as to which patients respond better to rhTSH. Currently, the lowest and most efficacious/effective dose of rhTSH is ∼0.03 mg. Studies comparing exogenous TSH with endogenous TSH are still required, in order to clarify the benefits and adverse effects of each type of treatment. It should be emphasized that rhTSH-stimulated 131I therapy is still an off-label treatment for MNG.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    • Search Google Scholar
    • Export Citation
  • 40

    Medeiros-Neto G, Marui S, Knobel M. An outline concerning the potential use of recombinant human thyrotropin for improving radioiodine therapy of multinodular goiter. Endocrine 2008 33 109117. (doi:10.1007/s12020-008-9077-7).

    • Search Google Scholar
    • Export Citation
  • 41

    Fast S, Nielsen VE, Grupe P, Boel-Jorgensen H, Bastholt L, Andersen PB, Bonnema SJ, Hegedus L. Prestimulation with recombinant human thyrotropin (rhTSH) improves the long-term outcome of radioiodine therapy for multinodular nontoxic goiter. Journal of Clinical Endocrinology and Metabolism 2012 97 26532660. (doi:10.1210/jc.2011-3335).

    • Search Google Scholar
    • Export Citation
  • 42

    Giusti M, Cappi C, Santaniello B, Ceresola E, Augeri C, Lagasio C, Minuto F. Safety and efficacy of administering 0.2 mg of recombinant human TSH for two consecutive days as an adjuvant to therapy with low radioiodine doses in elderly out-patients with large nontoxic multinodular goiter. Minerva Endocrinologica 2006 31 191209.

    • Search Google Scholar
    • Export Citation
  • 43

    Giusti M, Caputo M, Calamia I, Bagnara M, Ceresola E, Schiavo M, Mussap M, Ferone D, Minuto F, Bagnasco M. Long-term outcome of low-activity radioiodine administration preceded by adjuvant recombinant human TSH pretreatment in elderly subjects with multinodular goiter. Thyroid Research 2009 2 6. (doi:10.1186/1756-6614-2-6).

    • Search Google Scholar
    • Export Citation
  • 44

    Nielsen VE, Bonnema SJ, Boel-Jorgensen H, Veje A, Hegedus L. Recombinant human thyrotropin markedly changes the 131I kinetics during 131I therapy of patients with nodular goiter: an evaluation by a randomized double-blinded trial. Journal of Clinical Endocrinology and Metabolism 2005 90 7983. (doi:10.1210/jc.2004-1550).

    • Search Google Scholar
    • Export Citation
  • 45

    Nielsen VE, Bonnema SJ, Hegedus L. Transient goiter enlargement after administration of 0.3 mg of recombinant human thyrotropin in patients with benign nontoxic nodular goiter: a randomized, double-blind, crossover trial. Journal of Clinical Endocrinology and Metabolism 2006 91 13171322. (doi:10.1210/jc.2005-2137).

    • Search Google Scholar
    • Export Citation
  • 46

    Romão R, Rubio IGS, Tomimori EK, Camargo RY, Knobel M, Medeiros-Neto G. High prevalence of side effects after recombinant human thyrotropin-stimulated radioiodine treatment with 30 mCi in patients with multinodular goiter and subclinical/clinical hyperthyroidism. Thyroid 2009 19 945951. (doi:10.1089/thy.2008.0394).

    • Search Google Scholar
    • Export Citation
  • 47

    Silva MNC, Rubio IGS, Romao R, Gebrin EMMS, Buchpiguel C, Tomimori E, Camargo R, Cardia MS, Medeiros-Neto G. Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clinical Endocrinology 2004 60 300308. (doi:10.1046/j.1365-2265.2003.01918.x).

    • Search Google Scholar
    • Export Citation
  • 48

    Cohen O, Ilany J, Hoffman C, Olchovsky D, Dabhi S, Karasik A, Goshen E, Rotenberg G, Zwas ST. Low-dose recombinant human thyrotropin-aided radioiodine treatment of large, multinodular goiters in elderly patients. European Journal of Endocrinology 2006 154 243252. (doi:10.1530/eje.1.02094).

    • Search Google Scholar
    • Export Citation
  • 49

    Graf H. Multinodular goiter: pathogenesis and management. In Werner & Ingbar's The Thyroid, 10th edn, pp 635–649. Eds LE Braverman & DS Cooper. Philadelphia: Lippincott, 2013

  • 50

    Paz-Filho GJ, Mesa CO, Carvalho GA, Goedert CA, Graf H. Recombinant human TSH associated with radioiodine does not have further effects on thyroid volume and function after 2 years. Clinical Endocrinology 2008 69 345346. (doi:10.1111/j.1365-2265.2007.03165.x).

    • Search Google Scholar
    • Export Citation
  • 51

    Fast S, Hegedus L, Pacini F, Pinchera A, Leung AM, Vaisman M, Reiners C, Wemeau J-L, Huysmans DA, Harper W et al.. Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study. Thyroid 2014 24 727735. (doi:10.1089/thy.2013.0370).

    • Search Google Scholar
    • Export Citation
  • 52

    Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA et al.. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011 21 593646. (doi:10.1089/thy.2010.0417).

    • Search Google Scholar
    • Export Citation
  • 53

    Albino CC, Graf H, Sampaio AP, Vigário A, Paz-Filho GJ. Thiamazole as an adjuvant to radioiodine for volume reduction of multinodular goiter. Expert Opinion on Investigational Drugs 2008 17 17811786. (doi:10.1517/13543780802501325).

    • Search Google Scholar
    • Export Citation
  • 54

    Flores-Rebollar A, Ruiz-Juvera A, Lopez-Carrasco G, Gonzalez-Trevino O. Effect of 1110 MBq radioiodine in reducing thyroid volume in multinodular goiter: a new protocol. Journal of Clinical Medicine Research 2013 5 234238.

    • Search Google Scholar
    • Export Citation

 

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    Significant positive correlation between the degree of goiter volume reduction and the effective uCi/g activity of administered 131I (r=0.676, P=0.002).

  • View in gallery

    Scintigraphy before (A) and 24 h after the administration of 0.1 mg rhTSH in a single dose (B). Besides making the uptake of 131I more homogeneous, rhTSH increased the 24-h uptake from 4.5 to 39.3%.

  • View in gallery

    An example of goiter reduction. Computerized tomography with multiplanar reconstruction of a patient with multinodular substernal goiter treated with 30 mCi (1.11 MBq) radioactive iodine after 0.1 mg rhTSH. (A1) and (A2): baseline (thyroid volume 147 ml); (B1) and (B2): 1 year after treatment (thyroid volume 42 ml).

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    Bonnema SJ, Nielsen VE, Boel-Jorgensen H, Grupe P, Andersen PB, Bastholt L, Hegedus L. Improvement of goiter volume reduction after 0.3 mg recombinant human thyrotropin-stimulated radioiodine therapy in patients with a very large goiter: a double-blinded, randomized trial. Journal of Clinical Endocrinology and Metabolism 2007 92 34243428. (doi:10.1210/jc.2007-0501).

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    Bonnema SJ, Nielsen VE, Boel-Jorgensen H, Grupe P, Andersen PB, Bastholt L, Hegedus L. Recombinant human thyrotropin-stimulated radioiodine therapy of large nodular goiters facilitates tracheal decompression and improves inspiration. Journal of Clinical Endocrinology and Metabolism 2008 93 39813984. (doi:10.1210/jc.2008-0485).

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    Cubas ER, Paz-Filho GJ, Olandoski M, Goedert CA, Woellner LC, Carvalho GA, Graf H. Recombinant human TSH increases the efficacy of a fixed activity of radioiodine for treatment of multinodular goitre. International Journal of Clinical Practice 2009 63 583590. (doi:10.1111/j.1742-1241.2008.01904.x).

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    Fast S, Bonnema SJ, Hegedus L. Radioiodine therapy of benign non-toxic goitre. Potential role of recombinant human TSH. Annales d'Endocrinologie 2011 72 129135. (doi:10.1016/j.ando.2011.03.018).

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    Fast S, Nielsen VE, Bonnema SJ, Hegedus L. Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy. European Journal of Endocrinology 2009 160 517528. (doi:10.1530/EJE-08-0779).

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  • 19

    Graf H, Fast S, Pacini F, Pinchera A, Leung A, Vaisman M, Reiners C, Wemeau JL, Huysmans D, Harper W et al.. Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131I) therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2011 96 13681376. (doi:10.1210/jc.2010-1193).

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    Paz-Filho GJ, Mesa-Junior CO, Olandoski M, Woellner LC, Goedert CA, Boguszewski CL, Carvalho GA, Graf H. Effect of 30 mCi radioiodine on multinodular goiter previously treated with recombinant human thyroid-stimulating hormone. Brazilian Journal of Medical and Biological Research 2007 40 16611670. (doi:10.1590/S0100-879X2006005000186).

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    Nieuwlaat WA, Hermus AR, Sivro-Prndelj F, Corstens FH, Huysmans DA. Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters. Journal of Clinical Endocrinology and Metabolism 2001 86 53305336. (doi:10.1210/jcem.86.11.8014).

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    Fast S, Hegedus L, Grupe P, Nielsen VE, Bluhme C, Bastholt L, Bonnema SJ. Recombinant human thyrotropin-stimulated radioiodine therapy of nodular goiter allows major reduction of the radiation burden with retained efficacy. Journal of Clinical Endocrinology and Metabolism 2010 95 37193725. (doi:10.1210/jc.2010-0634).

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    Fast S, Nielsen VE, Bonnema SJ, Hegedus L. Dose-dependent acute effects of recombinant human TSH (rhTSH) on thyroid size and function: comparison of 0.1, 0.3 and 0.9 mg of rhTSH. Clinical Endocrinology 2010 72 411416. (doi:10.1111/j.1365-2265.2009.03650.x).

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    Bonnema SJ, Fast S, Hegedus L. Non-surgical approach to the benign nodular goiter: new opportunities by recombinant human TSH-stimulated 131I-therapy. Endocrine 2011 40 344353. (doi:10.1007/s12020-011-9542-6).

    • Search Google Scholar
    • Export Citation
  • 37

    Ceccarelli C, Antonangeli L, Brozzi F, Bianchi F, Tonacchera M, Santini P, Mazzeo S, Bencivelli W, Pinchera A, Vitti P. Radioiodine 131I treatment for large nodular goiter: recombinant human thyrotropin allows the reduction of radioiodine 131I activity to be administered in patients with low uptake. Thyroid 2011 21 759764. (doi:10.1089/thy.2010.0088).

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    • Export Citation
  • 38

    Fast S, Nielsen VE, Grupe P, Bonnema SJ, Hegedus L. Optimizing 131I uptake after rhTSH stimulation in patients with nontoxic multinodular goiter: evidence from a prospective, randomized, double-blind study. Journal of Nuclear Medicine 2009 50 732737. (doi:10.2967/jnumed.108.060152).

    • Search Google Scholar
    • Export Citation
  • 39

    Ceccarelli C, Brozzi F, Bianchi F, Santini P. Role of recombinant human TSH in the management of large euthyroid multinodular goitre: a new therapeutic option? Pros and cons. Minerva Endocrinologica 2010 35 161171.

    • Search Google Scholar
    • Export Citation
  • 40

    Medeiros-Neto G, Marui S, Knobel M. An outline concerning the potential use of recombinant human thyrotropin for improving radioiodine therapy of multinodular goiter. Endocrine 2008 33 109117. (doi:10.1007/s12020-008-9077-7).

    • Search Google Scholar
    • Export Citation
  • 41

    Fast S, Nielsen VE, Grupe P, Boel-Jorgensen H, Bastholt L, Andersen PB, Bonnema SJ, Hegedus L. Prestimulation with recombinant human thyrotropin (rhTSH) improves the long-term outcome of radioiodine therapy for multinodular nontoxic goiter. Journal of Clinical Endocrinology and Metabolism 2012 97 26532660. (doi:10.1210/jc.2011-3335).

    • Search Google Scholar
    • Export Citation
  • 42

    Giusti M, Cappi C, Santaniello B, Ceresola E, Augeri C, Lagasio C, Minuto F. Safety and efficacy of administering 0.2 mg of recombinant human TSH for two consecutive days as an adjuvant to therapy with low radioiodine doses in elderly out-patients with large nontoxic multinodular goiter. Minerva Endocrinologica 2006 31 191209.

    • Search Google Scholar
    • Export Citation
  • 43

    Giusti M, Caputo M, Calamia I, Bagnara M, Ceresola E, Schiavo M, Mussap M, Ferone D, Minuto F, Bagnasco M. Long-term outcome of low-activity radioiodine administration preceded by adjuvant recombinant human TSH pretreatment in elderly subjects with multinodular goiter. Thyroid Research 2009 2 6. (doi:10.1186/1756-6614-2-6).

    • Search Google Scholar
    • Export Citation
  • 44

    Nielsen VE, Bonnema SJ, Boel-Jorgensen H, Veje A, Hegedus L. Recombinant human thyrotropin markedly changes the 131I kinetics during 131I therapy of patients with nodular goiter: an evaluation by a randomized double-blinded trial. Journal of Clinical Endocrinology and Metabolism 2005 90 7983. (doi:10.1210/jc.2004-1550).

    • Search Google Scholar
    • Export Citation
  • 45

    Nielsen VE, Bonnema SJ, Hegedus L. Transient goiter enlargement after administration of 0.3 mg of recombinant human thyrotropin in patients with benign nontoxic nodular goiter: a randomized, double-blind, crossover trial. Journal of Clinical Endocrinology and Metabolism 2006 91 13171322. (doi:10.1210/jc.2005-2137).

    • Search Google Scholar
    • Export Citation
  • 46

    Romão R, Rubio IGS, Tomimori EK, Camargo RY, Knobel M, Medeiros-Neto G. High prevalence of side effects after recombinant human thyrotropin-stimulated radioiodine treatment with 30 mCi in patients with multinodular goiter and subclinical/clinical hyperthyroidism. Thyroid 2009 19 945951. (doi:10.1089/thy.2008.0394).

    • Search Google Scholar
    • Export Citation
  • 47

    Silva MNC, Rubio IGS, Romao R, Gebrin EMMS, Buchpiguel C, Tomimori E, Camargo R, Cardia MS, Medeiros-Neto G. Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clinical Endocrinology 2004 60 300308. (doi:10.1046/j.1365-2265.2003.01918.x).

    • Search Google Scholar
    • Export Citation
  • 48

    Cohen O, Ilany J, Hoffman C, Olchovsky D, Dabhi S, Karasik A, Goshen E, Rotenberg G, Zwas ST. Low-dose recombinant human thyrotropin-aided radioiodine treatment of large, multinodular goiters in elderly patients. European Journal of Endocrinology 2006 154 243252. (doi:10.1530/eje.1.02094).

    • Search Google Scholar
    • Export Citation
  • 49

    Graf H. Multinodular goiter: pathogenesis and management. In Werner & Ingbar's The Thyroid, 10th edn, pp 635–649. Eds LE Braverman & DS Cooper. Philadelphia: Lippincott, 2013

  • 50

    Paz-Filho GJ, Mesa CO, Carvalho GA, Goedert CA, Graf H. Recombinant human TSH associated with radioiodine does not have further effects on thyroid volume and function after 2 years. Clinical Endocrinology 2008 69 345346. (doi:10.1111/j.1365-2265.2007.03165.x).

    • Search Google Scholar
    • Export Citation
  • 51

    Fast S, Hegedus L, Pacini F, Pinchera A, Leung AM, Vaisman M, Reiners C, Wemeau J-L, Huysmans DA, Harper W et al.. Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study. Thyroid 2014 24 727735. (doi:10.1089/thy.2013.0370).

    • Search Google Scholar
    • Export Citation
  • 52

    Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA et al.. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011 21 593646. (doi:10.1089/thy.2010.0417).

    • Search Google Scholar
    • Export Citation
  • 53

    Albino CC, Graf H, Sampaio AP, Vigário A, Paz-Filho GJ. Thiamazole as an adjuvant to radioiodine for volume reduction of multinodular goiter. Expert Opinion on Investigational Drugs 2008 17 17811786. (doi:10.1517/13543780802501325).

    • Search Google Scholar
    • Export Citation
  • 54

    Flores-Rebollar A, Ruiz-Juvera A, Lopez-Carrasco G, Gonzalez-Trevino O. Effect of 1110 MBq radioiodine in reducing thyroid volume in multinodular goiter: a new protocol. Journal of Clinical Medicine Research 2013 5 234238.

    • Search Google Scholar
    • Export Citation