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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2137
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1317-1322
Copyright © 2006 by The Endocrine Society

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

Viveque Egsgaard Nielsen, Steen J. Bonnema and Laszlo Hegedüs

Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Viveque E. Nielsen, M.D., Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: viveque.egsgaard{at}ouh.fyns-amt.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Recombinant human (rh) TSH, in doses from 0.01 to 0.9 mg, has been used to augment the effect of radioiodine (131I) therapy in patients with a benign nontoxic nodular goiter. Transient thyroid enlargement and thyrotoxicosis may be seen following 131I therapy.

Aim: The aim of the study was to investigate whether rhTSH per se causes goiter enlargement, until now an issue evaluated only in healthy nongoitrous subjects.

Methods: In random order, 10 patients with nontoxic nodular goiter [mean 39.8 ± 20.5 (SD) ml] received either 0.3 mg rhTSH or isotonic saline in a double-blinded crossover design. Thyroid volume (by ultrasound) and function were closely monitored during the following 28 d.

Results: Saline injection did not affect thyroid function or size. After rhTSH, median serum TSH increased from baseline 0.97 mU/liter (range 0.39–1.56) to 37.0 mU/liter (range 18.5–55.0) at 24 h (P < 0.01), with a subsequent decline to subnormal levels at d 7. Mean free T4 and free T3 increased significantly from baseline to a maximum at 48 h. Twenty-four hours after rhTSH, the mean goiter volume was significantly increased by 9.8 ± 2.3% (SEM) (P = 0.01) and after 48 h by 24.0 ± 5.1% (P = 0.002). The goiter enlargement had reverted at d 7. Nine patients had symptoms of hyperthyroidism and/or cervical compression after rhTSH, as opposed to one during placebo treatment (P < 0.02).

Conclusions: A transient average goiter enlargement of up to 24% is seen after 0.3 mg rhTSH. This may lead to a significant cervical compression when used for augmentation of 131I therapy in patients with goiter. The use of lower doses of rhTSH needs to be explored.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
IN 1960, DANOWSKI et al. (1) described that bovine TSH, at that time used as the only available external source to elevate circulating TSH levels in patients with differentiated thyroid carcinoma, resulted in development of thyroid swelling and cervical tenderness in 10 of 21 healthy male subjects.

Today, recombinant human (rh) TSH is used in patients with differentiated thyroid carcinoma and is generally well tolerated, but case reports of local reactions such as tumor swelling and pain from metastases (2, 3, 4, 5) have been published. Recently we investigated the effect of rhTSH on thyroid size in healthy nongoitrous subjects (6) and showed that a single injection of 0.9 mg rhTSH resulted in a short-lived significant thyroid swelling of 23% after 24 h peaking at 35% after 48 h.

In recent years, the use of rhTSH combined with radioiodine (131I) in the treatment of benign thyroid diseases has received increasing attention due to the ability of rhTSH to stimulate thyroid radioiodine uptake (7, 8, 9, 10, 11) and thereby possibly enhancing the effect of 131I therapy (12). We have shown that the conventional use of 131I in multinodular goiter does not result in any significant acute average enlargement of the thyroid gland (13, 14, 15), although a volume increment between 15 and 25% occasionally may be seen (13, 14). Until now no study has evaluated the goiter size within the first days after rhTSH and 131I therapy. In the study by Nieuwlaat et al. (16), a slight but statistically significant transient goiter enlargement of 5% was seen 1 wk after 0.03 mg rhTSH and 131I therapy, a finding very similar to that observed without rhTSH prestimulation (13, 14, 15).

To what extent the increment in thyroid volume, after stimulation with rhTSH in healthy subjects, can be extrapolated to patients with nodular goiter is at present unclarified but certainly of great clinical relevance before routine use of rhTSH in combination with 131I therapy can be recommended. Thus, the aim of our study was to investigate the effect of 0.3 mg rhTSH on thyroid function and ultrasonically determined goiter volume in the early phase after rhTSH administration in patients with benign nontoxic nodular goiter.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We studied 10 patients (nine females and one male) with asymptomatic benign nontoxic nodular goiter. Patients were recruited in our outpatient clinic and the diagnosis was obtained by clinical examination, ultrasonography, and 99mTc-pertechnetate scintigraphy. We selected patients with asymptomatic goiter because these patients did not have any immediate need of treatment. Their median age was 55 yr (range 35–67 yr). They had a mean goiter volume of 39.8 ± 20.5 ml (SD). None had previously received any treatment for their nodular goiter. Three patients (30%) had subnormal TSH values (serum TSH values between 0.1 and 0.4 mU/liter). The remaining seven patients had a normal serum TSH as well as free T4 (FT4) and free T3 (FT3). None had thyroid peroxidase antibodies (TPOab) or TSH receptor antibodies (TSHRab). Four had thyroglobulin (Tg) antibodies (Tgab) and were excluded when calculating data on serum Tg. Exclusion criteria were obstructive symptoms (i.e. stridor), overt hyperthyroidism, pregnancy, breast-feeding, and ischemic heart disease (due to concern of cardiac side effects related to the known transient thyrotoxicosis after rhTSH stimulation). No individual had any other medical problems or took any drug known to affect the function and size of the thyroid gland. The study was approved by the Local Ethics Committee of the County of Funen, Denmark (trial number 2003-0128), and subjects were included after giving oral and written consent.

Study design

The study was performed in a randomized, placebo-controlled, double-blinded, crossover design. Randomization was performed by an independent pharmacist at the hospital, and each subject was examined twice and received in random order either 0.3 mg rhTSH or isotonic saline, injected im in the gluteal region. Freeze-dried rhTSH (vials containing 0.9 mg rhTSH) (Thyrogen; Genzyme Transgenic Corp., Cambridge, MA) was reconstituted with 3 ml isotonic saline. Of this dilution, 0.3 mg rhTSH corresponds to 1 ml. An amount of 0.3 mg rhTSH was chosen because this dose is used in some of our ongoing studies concerning the goiter reducing effect of rhTSH in combination with 131I therapy. Thyroid size (by ultrasound) and function (serum levels of TSH, FT4, FT3, and Tg) were evaluated at baseline and 24 and 36 h as well as 2, 3, 7, and 28 d after administration of rhTSH or placebo. Each of the two study periods was 28 d, and the second period was commenced immediately after the first. With the exception of the 36-h investigation (between 2000 and 2100 h), all were performed between 0800 and 0900 h. TPOab, TSHRab, and Tgab were measured at baseline and 28 d after injection of isotonic saline and rhTSH.

Measurements

The total thyroid volume was measured, as previously described (17), by a precise and accurate planimetric ultrasonic scanning procedure, using a 5.5-MHz compound scanner (type 1846; Brüel & Kjær, Copenhagen, Denmark). In each subject, measurements were performed by the same operator who was blinded toward previous measurements. The average intraobserver variation of this method is 5% (17). The mean thyroid volume in an adult Danish population without clinically overt goiter is 18.5 ml (range 9.6–27.6 ml) (17).

Serum TSH was measured using a time-resolved fluoroimmunometric assay (AutoDELFIA human TSH ultra, reference interval 0.30–4.00 mU/liter; PerkinElmer/Wallac, Turku, Finland). Serum FT4 and FT3 were determined using the AutoDELFIA FT4 and FT3 kits (reference intervals 9.9–17.7 and 4.3–7.4 pmol/liter, respectively; PerkinElmer/Wallac). Serum Tg was measured by solid-phase, two-site, time-resolved fluoroimmunoassays (DELFIA Tg kit, PerkinElmer/Wallac). Reference range is 2.0–70.0 µg/liter. TPOab and Tgab were measured by solid phase, two step, time-resolved fluoroimmunoassays (AutoDELFIA TPOab kit and human Tgab kit, respectively, PerkinElmer/Wallac). Values above 60 U/ml are regarded as positive for both antibodies. TSHRab was measured using a radioreceptor assay (DYNOtest TRAK human kit; BRAHMS Diagnostica Gmbh, Berlin, Germany). TSHRab values less than 1 IU/liter are regarded as negative, values greater than 2 IU/liter as positive. For further details concerning the assays, please see our article regarding healthy nongoitrous subjects (6). All sera were frozen at –20 C and measured in the same relevant assay.

Statistics

A sample size of minimum seven individuals was calculated to ensure detection of a between-group difference of 15% with SD of 10% of the relative goiter swelling and accepting a type I error of 5% and a type II error of 10%. The SPSS 13 statistical software program (SPSS Inc., Chicago, IL) was used for analysis. Data are presented as medians (range) or means (±SD or SEM), depending on the normality (tested by the Kolmogorov-Smirnov test). A two-way ANOVA was performed to test for an overall difference between groups. A one-way repeated-measure ANOVA or the Friedmann’s test (depending on the normality on the data) was used to test for within-group differences. Calculation of the percent mean difference was based on log-transformed data, thereby making a decline of a variable equivalent to an increase. Simple linear regression was used to measure the linear relationship between relevant variables, which were log transformed, if appropriate. Differences in adverse effects between treatments were evaluated by McNemar’s test. The level of statistical significance was chosen as P < 0.05.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Six subjects were randomized to receive rhTSH before placebo, and thus four subjects were treated in the opposite order.

Thyroid volume (Fig. 1Go)

The goiter volume before injection of rhTSH and placebo was 40.5 ± 21.1 (SD) and 39.1 ± 21.0 ml, respectively (P = 0.88). After injection of placebo, the goiter volume did not change significantly from baseline at any time during the following 28 d. In contrast, stimulation with rhTSH resulted in a significant increase of the goiter volume to 45.0 ± 25.0 (SD) ml after 24 h (P = 0.01), 50.0 ± 27.0 ml at 36 h (P = 0.01), and 50.4 ± 25.1 ml after 48 h (P = 0.002), corresponding to an increase of 9.8 ± 2.3 (SEM), 22.0 ± 4.7, and 24.0 ± 5.1%, respectively. The goiter enlargement had reverted at d 7 and remained so at d 28. Thus, the maximum thyroid enlargement in each individual appeared between d 1 and 3.


Figure 1
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  		FIG. 1. Changes in thyroid volume after administration of 0.3 mg rhTSH (dashed lines) and isotonic saline (solid lines). Absolute values are given in the top panel, relative values in the bottom panel. *, P = 0.01, **, P = 0.002 (compared with baseline); §, one patient was absent at this time.

 
Thyroid function and thyroglobulin response (Fig. 2Go)

Serum levels of FT4, FT3, and Tg did not at any time divert significantly from baseline after placebo injection. For unknown reasons serum TSH was slightly increased at d 28 (1.11 mU/liter, range 0.34–1.35; P = 0.007), compared with baseline values. Following rhTSH injection, median serum TSH increased from 0.97 mU/liter (range 0.39–1.56 mU/liter) at baseline to a maximum of 37.0 mU/liter (range 18.5–55.0 mU/liter) at 24 h (P < 0.01). Thereafter serum TSH declined rapidly to 0.14 mU/liter (range 0.09–0.24; P < 0.01) at d 7 and 0.45 mU/liter (range 0.08–1.19: P < 0.01) at d 28.


Figure 2
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  		FIG. 2. Changes in serum levels of TSH, FT4, FT3, and Tg after administration of 0.3 mg rhTSH (dashed lines) and isotonic saline (solid lines). Values are given as means ± SD (serum FT4 and FT3) and median and quartiles (serum TSH and Tg). Serum TSH and Tg values are logarithmically transformed. *, P < 0.01, **, P < 0.004, ***, P < 0.0004 (compared with baseline); #, P = 0.007 (compared with baseline).

 
Parallel to the rise in serum TSH, but with a small time delay, increased levels of serum FT4 and FT3 were observed. At 24 h, both variables were significantly elevated, peaking at 48 h at which time serum FT4 was 31.3 ± 10.6 pmol/liter (SD) (P = 0.0003, compared with 13.5 ± 1.72 pmol/liter at baseline), and serum FT3 was 18.5 ± 6.6 pmol/liter (SD) (P = 0.0002, compared with 6.4 ± 0.6 pmol/liter at baseline). These figures correspond to 122.6 ± 8.3% (SEM) (FT4) and 69.1 ± 13.9% (FT3), respectively, above baseline levels. At d 7, the thyroid hormone levels were still significantly elevated [serum FT4: 20.9 ± 5.0 pmol/liter (SD), P = 0.0004; serum FT3: 9.1 ± 2.4 pmol/liter (SD), P < 0.01], probably explaining the decrease in serum TSH at this time.

The serum Tg pattern showed great individual variation after rhTSH stimulation. On average, median serum Tg increased from 51 µg/liter (range 8–114) to 248.5 µg/liter (range 42–651; P < 0.0001) at 24 h, with levels peaking at 48 h (552.0 µg/liter, range 72–1990; P < 0.0001). By d 7 the median serum Tg was still slightly elevated (176 µg/liter, range 13–659, P = 0.004). There was no correlation between the maximum increase in thyroid volume after rhTSH stimulation and the peak levels of serum TSH, FT4, FT3, or Tg. None developed antibodies against Tg, TPO, or TSHR.

Adverse effects

In the early period following injection, rhTSH caused various adverse effects in the majority of subjects. Symptoms related to possible thyroid hyperfunction (tachycardia, increased appetite, restlessness, perspiration, headache, nausea, and myalgias) were recorded in five patients after rhTSH, compared with none after saline. Symptoms related to possible thyroid growth (visual enlargement, thyroid tenderness, or pain) were evident in six patients after rhTSH, compared with one (a sensation of globulus) after saline. None of the six affected patients had any respiratory problems during this period. In all, nine of 10 (90%), compared with one of 10 (10%) had side effects (P < 0.02) after rhTSH and isotonic saline, respectively. Although self-limiting, the symptoms and discomfort appeared in some individuals as early as 4 h (median 24 h, range 4–36 h) after rhTSH stimulation and lasted up to 96 h (median 72 h, range 24–96 h). The symptoms recorded after 4 h were related to the increase in serum TSH (headache and restlessness), whereas the symptoms at 96 h were related to thyroid growth (anterior neck tenderness and pain).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present study is the first to describe, in detail, the acute effect of rhTSH stimulation on goiter volume in patients with nontoxic nodular goiter. This issue is of importance in view of the growing interest in using rhTSH to augment the effect of 131I therapy in patients with benign goiter (8, 12, 16, 18, 19).

A single injection of 0.3 mg rhTSH resulted in a significant and symptomatic thyroid swelling that appeared, on average, 24 h after injection and peaked after 48 h. On clinical examination, this profound and short-lived stimulation of the thyroid, also evidenced by a concomitant increase in serum Tg, did not cause any respiratory distress. However, we cannot exclude that there was an impact on the tracheal cross-sectional area because we did not perform tracheal imaging (computed tomography or magnetic resonance imaging) or pulmonary function tests. Although normal thyroid glands may respond differently to rhTSH, compared with nodular goiters, we found very similar qualitative effects on thyroid volume and function in our previous study of healthy subjects (6), receiving 0.9 mg rhTSH, and in patients with goiter, receiving 0.3 mg rhTSH. Thus, in healthy subjects the maximum increase in thyroid volume was 35% after 48 h, compared with 24% in the goiter patients. Likewise, the effects appeared within the first days and had reverted at d 7 in healthy subjects as well as in goiter patients. We earlier hypothesized that the acute rhTSH induced thyroid enlargement is caused by intravascular and interstitial fluid accumulation. The less pronounced relative thyroid swelling observed in the present study may be due to the lower dose of rhTSH (0.3 vs. 0.9 mg) and/or a poorer vascularization in the thyroid due to nodularity and localized cystic/fibrotic degeneration of the gland.

The effect of various doses of rhTSH on thyroid function has previously been investigated (6, 9, 11, 20). Both in healthy subjects and patients with nodular goiter different doses of rhTSH (0.01, 0.03, 0.3, and 0.9 mg) have been used, and the same patterns in the various biochemical markers have been observed. In the present study, the changes in serum levels of FT4, FT3, and Tg are similar to those seen in earlier investigations. Compared with the only other study, investigating thyroid function in patients with nodular nontoxic goiter (9), a clear dose-response effect seems to exist because a greater response in serum levels of T4, T3, and Tg is achieved when administering 0.3 mg rhTSH, compared with 0.01 or 0.03 mg (9). Thus, in the study by Huysmans et al. (9), the increases in serum FT4 and FT3 levels were blunted and most patients retained thyroid hormone levels within the normal range, as opposed to increases of 123 (serum FT4) and 69% (serum FT3) above baseline values in the present study.

As in the healthy subjects (6), various adverse effects, related to both thyroid hyperfunction and pressure symptoms, were seen in the majority of goiter patients in the early period following rhTSH injection. However, despite the use of a lower rhTSH dose and less pronounced thyroid swelling following rhTSH, thyroid pain and tenderness had a longer duration in goiter patients, compared with healthy subjects (96 h in the goiter patients vs. 48 h in healthy subjects). This can probably be explained by the fact that the thyroid volume at baseline was considerably larger in the goiter patients, compared with healthy subjects (40 vs. 15 ml). Whether inflammatory processes are involved remains to be clarified, but a rapid response to nonsteroidal antiinflammatory drugs in our previous study (6) favors this possibility.

Recently several studies have suggested that rhTSH may improve the effect of 131I therapy in patients with benign nodular goiter (8, 12, 16, 18, 19). Apart from the study by Nieuwlaat et al. (16), using very small rhTSH doses, to minimize the risk of adverse effects, little attention has focused on safety issues. The fact that upper airway obstruction is present in a large fraction of patients with goiter, despite absence of symptoms (21), is often overlooked. Furthermore, conventional 131I therapy, per se, may cause a transient 15–25% goiter enlargement within the first week after 131I (13, 14). Consequently, our findings have important clinical implications because the use of rhTSH, combined with 131I therapy in patients with goiter, may potentially cause serious respiratory problems in susceptible individuals, due to a possible additive or even synergistic effect. The study by Silva et al. (19) supports our concern by reporting that side effects after 131I therapy in combination with rhTSH are more common than without rhTSH. Thus, more patients pretreated with rhTSH suffered from local cervical pain (52 vs. 23%) during the 131I therapy (19). Whether this was related to an early thyroid enlargement after 131I therapy or secondary to rhTSH cannot be untangled because goiter size was not measured during the relevant period.

From the above, it follows that we discourage the indiscriminate use of high rhTSH doses when treating patients with an intact thyroid gland until the underlying mechanisms leading to, and the consequences of, this pronounced thyroid swelling have been disclosed. It is also important to address the possibility of preventing this potentially serious side effect with, for example, mild analgesics or corticosteroids, as often used in the context of disseminated thyroid malignancy (3, 4, 5). Furthermore, the acute effect of rhTSH in patients with a large goiter needs to be explored because these patients, at least in theory, have a smaller tracheal cross-sectional area, compared with patients with a smaller goiter, and therefore may be more prone to adverse effects. Finally, the optimal dose of rhTSH before 131I therapy could well be less than 0.3 mg, as indicated by recent studies in nodular goiter (9, 12, 16). Whether such a dose reduction also leads to reduction in thyroid swelling remains to be investigated, as does the possible effect of fractioning the rhTSH dose.


   Acknowledgments
 
We thank the Department of Clinical Chemistry, Odense University Hospital, for performing the biochemical analyses.


   Footnotes
 
This study was supported by research grants from The Agnes and Knut Mørk Foundation, The Research Foundation of the County of Funen, The Medical Research Foundation of the County of Funen, The Novo Nordic Foundation, The A. P. Møller Relief Foundation, chief physician Johan Boserup and wife Lise Boserup’s Foundation, manager Jacob Madsen and wife Olga Madsen’s Foundation, The Institute of Clinical Research-University of Southern Denmark, and The Council of Chief Physicians’ Foundation at Odense University Hospital.

The authors have no potential conflicts of interest to disclose.

First Published Online January 24, 2006

Abbreviations: FT3, Free T3; FT4, free T4; rh, recombinant human; Tg, thyroglobulin; Tgab, Tg antibodies; TPOab, thyroid peroxidase antibodies; TSHRab, TSH receptor antibodies.

Received September 26, 2005.

Accepted January 17, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals