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Effects of 0.9 mg Recombinant Human Thyrotropin on Thyroid Size and Function in Normal Subjects: A Randomized, Double-Blind, Cross-Over Trial

Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, 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 Subjects and Methods Results Discussion References

 
The effect of recombinant human TSH (rhTSH) on thyroid function and ultrasonically determined thyroid volume was investigated in nine healthy euthyroid male volunteers. Each received either 0.9 mg rhTSH or isotonic saline in a randomized order, and thyroid volume and function were closely monitored during the following 28 d. No significant changes were observed after saline injection. After rhTSH stimulation, the median serum TSH increased from 2.03 mU/liter (range, 0.99–3.07 mU/liter) to more than 200 mU/liter (range, 78.9 to >200.0 mU/liter) after 4 h, with a subsequent rapid decline. Mean (±SEM) serum free T₄ and free T₃ peaked at 48 h with levels 204.7 ± 26.1% and 226.9 ± 31.4%, respectively, above baseline (P < 0.001). Twenty-four hours after rhTSH stimulation, mean (±SEM) thyroid volume was significantly increased by 23.3 ± 5.8% (P = 0.003) and after 48 h by 35.5 ± 18.4% (P = 0.02). On d 4 the mean thyroid enlargement had reverted to baseline values. One individual developed a 90-ml tender thyroid enlargement (initially 21 ml) 36 h after rhTSH administration, associated with a very high level of serum thyroglobulin. It is concluded that 0.9 mg rhTSH may result in a profound stimulation of not only thyroid function but also of thyroid size, appearing in the period 1–4 d after injection. Further dose-response studies are needed to clarify the potential hazards before routine use, for example in the context of ¹³¹I therapy and goiter.

	Introduction

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RECOMBINANT HUMAN TSH (rhTSH) was originally synthesized for the use in the postoperative monitoring of differentiated thyroid cancer (1). In this setting, stimulation with rhTSH is known to increase ¹³¹I uptake and thyroglobulin (Tg) release from the tumor remnants and/or metastases. In the case of nontoxic multinodular goiter, which is a much more frequent disorder, the ideal treatment is under debate (2). At present, clinicians favor L-T₄ suppressive therapy (3, 4) despite little evidence to support this strategy (2). Other treatment modalities are thyroidectomy and ¹³¹I therapy. Although the latter treatment is frequently used in some countries (3), its effectiveness is hampered by a low thyroid radioiodine uptake (RAIU), especially in areas with a high iodine intake. With the availability of rhTSH, the possibility of ¹³¹I therapy in benign thyroid diseases has received increasing attention. Besides being able to stimulate thyroid function and RAIU in subjects with an intact thyroid gland (5, 6, 7), it was recently suggested, in uncontrolled studies, that rhTSH may enhance the effect of ¹³¹I therapy in patients with a nodular nontoxic goiter (8, 9). Although these are very exciting reports, the use of rhTSH in patients with an intact thyroid gland may pose serious problems, particularly in the context of ¹³¹I therapy. Thus, it has previously been shown that stimulation with bovine TSH may result in an acute thyroid swelling (10), and recently it was reported that rhTSH may cause a critical tumor expansion in patients with metastases from differentiated thyroid carcinomas (11, 12, 13, 14, 15, 16). Before rhTSH gains a more widespread use for improvement of ¹³¹I therapy in patients with an intact thyroid, it must be clarified whether this agent may cause acute, clinically relevant thyroid gland enlargement. Although the effect of rhTSH has previously been investigated in subjects with an intact thyroid gland, demonstrating a doubling of the RAIU, the impact on thyroid volume has not been explored. In the present study we focus on the changes in ultrasonically determined thyroid size in the early phase after the administration of 0.9 mg rhTSH in healthy euthyroid male subjects.

	Subjects and Methods

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Subjects

We studied nine healthy male volunteers (median age, 33 yr; range, 22–50 yr) without evidence of thyroid disease. All had normal serum TSH and thyroid hormone levels, absence of thyroid autoantibodies [anti-Tg antibodies (anti-Tgab), antithyroid peroxidase antibodies (anti-TPOab), and anti-TSH receptor antibodies (TSH-Rab)], normal thyroid size (range, 10–22 ml) and morphology by ultrasonography. Only men were examined, because the volume of the thyroid gland is known to vary with the menstrual cycle (17). No individual had any medical problems or took drugs 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, and subjects were included after giving oral and written consent.

Study design and measurements

The study was performed in a randomized, placebo-controlled, double-blind, cross-over set-up. Each subject was examined twice and received in random order either 0.9 mg rhTSH or isotonic saline, injected im in the gluteal region. An amount of 0.9 mg rhTSH was chosen because this dose has been employed (usually administrated twice) in most previous studies of this drug (12, 14). Randomization was performed by an independent pharmacist at the hospital. Thyroid size was determined, and blood tests [serum TSH, free T₄ (FT₄), free T₃ (FT₃), and thyroglobulin (Tg)] were performed at baseline, 4 and 24 h, as well as 2, 4, 7, and 28 d after the administration of rhTSH or placebo. Each of the two study periods was 28 d, and the second period began immediately after the first. With the exception of the 4-h investigation, all were performed between 0800 and 0900 h. Anti-TPOab and anti-Tgab were measured at baseline and 28 d after the injection of isotonic saline and rhTSH. In addition, 24-h urinary iodine was collected on the day of injection and after 2, 7, and 28 d. Subjects did not receive iodine-restricted food, and no specific instructions were given regarding iodine intake during the protocol.

The total thyroid volume was measured, as previously described (18), 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 to previous measurements. The average intraobserver variation of this method is 5% (18). The mean thyroid volume in an adult population without clinically overt goiter is 18.5 ml (range, 9.6–27.6 ml) (18).

Serum TSH was measured using a time-resolved fluoroimmunometric assay (AutoDELFIA Human TSH Ultra, PerkinElmer/Wallac, Turku, Finland; reference interval, 0.30–4.00 mU/liter). The intra- and interassay coefficients of variation (CVs) at serum TSH concentrations of 0.046–17.6 mU/liter were 1.3–4.7% and 1.7–3.7%, respectively. Serum FT₄ and serum FT₃ were determined using the AutoDELFIA FT₄ and FT₃ kits (PerkinElmer/Wallac; reference intervals, 9.9–17.7 and 4.3–7.4 pmol/liter, respectively). The intra- and interassays CVs for FT₄ at serum concentrations of 9.2–19.2 pmol/liter were 1.3–2.0% and 3.9–5.4%, respectively, and the corresponding intra- and interassay CVs for FT₃ at serum concentrations of 4.7–9.7 pmol/liter were 3.9–5.0% and 2.9–4.2%, respectively. Serum Tg was measured by solid phase, two-site, time-resolved fluoroimmunoassays (DELFIA Tg kit, PerkinElmer/Wallac; reference range, 2.0–70.0 µg/liter). The intra- and interassay CVs for Tg at serum concentrations of 3.0–700 µg/liter were 2.9–3.0% and 3.8–4.8%, respectively.

Anti-TPOab and anti-Tgab were measured by solid phase, two-step, time-resolved fluoroimmunoassays (AutoDELFIA TPOab kit and human Tgab kit, respectively, PerkinElmer/Wallac). The intra- and interassay CVs for anti-TPOab and anti-Tgab in the range 50–155 U/ml were 3.2–8.4% and 3.8–10.1%, respectively. Values above 60 U/ml were regarded as positive for both antibodies. TSH-Rab was measured using a radioreceptor assay (DYNOtest TRAK human kit, BRAHMS Diagnostica Gmbh, Berlin, Germany). TSH-Rab values less than 1 IU/liter were regarded as negative; values more than 2 IU/liter were regarded as positive. The interassay CV at serum concentrations of 1.1–26.9 IU/liter ranged from 3.9–14.1%.

Urinary iodine was measured by the ceri/arsen method after alkaline ashing (19). To ensure that the 24-h sample was complete, urinary creatinine was measured simultaneously by a kinetic Jaffé method (20). The 24-h urinary iodine and creatinine excretions were calculated by multiplying the concentrations by the 24-h urinary volume.

All sera and urine samples were frozen at –20 C and measured in the same relevant assay.

Statistics

The STATA statistical software program was used for analysis of the data. Data are presented as medians (range) or means (±SD or ±SEM) depending on the normality of the data. Nonparametric or parametric (ANOVA) statistical tests were used to test treatment effects. Simple regression analyses were used to test correlations. Differences in adverse effects between the two groups were evaluated by a one-sided ² test. The level of statistical significance was as P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Five subjects were randomized to receive rhTSH before placebo, and thus, four subjects were treated in the opposite order.

Thyroid volume (Fig. 1)

The baseline thyroid volumes were 14.1 ± 2.7 and 15.8 ± 2.8 (±SD) ml before the injections of placebo and rhTSH, respectively (P = 0.19). After the injection of placebo, thyroid 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 in thyroid volume to 19.6 ± 4.6 ml (P = 0.003) after 24 h and to 22.3 ± 13.6 ml (P = 0.02, by Wilcoxon test) after 48 h, corresponding to 23.3 ± 5.8% and 35.5 ± 18.4% (±SEM), respectively. On d 4 the mean thyroid enlargement had reverted, and after 28 d the gland was reduced significantly compared with the baseline value (13.4 ± 2.2 ml, a reduction of 14.7 ± 3.8%; P = 0.005). The maximum thyroid enlargement in each individual occurred between d 1 and 4. One individual developed a very profound and tender thyroid enlargement between 24 and 30 h after the administration of rhTSH and was seen at our clinic 36 h after the injection. Determined ultrasonically, his thyroid gland was 90 ml, with a universally hypoecchogenic pattern. Using color-Doppler sonography, intrathyroidal blood flow was clearly decreased, compatible with a thyroiditis-like condition. The symptoms were promptly and efficiently treated with a nonsteroidal antiinflammatory drug (NSAID), and 72 h after administration of rhTSH the thyroid gland was no longer enlarged (17.5 ml vs. initially 21.0 ml). As we intervened with NSAID, we do not know what the real 48 h value would have been, and it is most likely that the measured value of 57.5 ml is artificially low. Omitting this individual who experienced this profound response to rhTSH stimulation, clearly an outlier in this setting, did not affect the overall results, which still revealed a significant increase in thyroid size at 24 h (18.4 ± 3.2 ml; P < 0.005; n = 8) as well as at 48 h (18.0 ± 3.7 ml; P = 0.03; n = 8).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Changes in thyroid volume after administration of 0.9 mg rhTSH (dashed lines) and isotonic saline (solid lines). Top, Absolute values; bottom, relative values. *, P 0.005; ** P = 0.02 (compared with baseline).

Thyroid function and Tg response (Fig. 2)

The serum level (s-) of TSH, FT₄, FT₃ and Tg did not at any time change significantly from baseline after placebo injection. After rhTSH injection, median s-TSH rose from 2.03 mU/liter (range, 0.99–3.07 mU/liter) to more than 200.0 mU/liter (range, 78.9 to >200.0 mU/liter) after 4 h. Thereafter, s-TSH declined rapidly, resulting in a slightly suppressed level 7 d after injection (median, 0.23 mU/liter; P < 0.01 compared with baseline). Parallel to the rise in s-TSH, but with a small time delay, increased levels of s-FT₄ and s-FT₃ were observed. At 4 h both variables were significantly elevated, and the serum levels peaked 48 h after rhTSH administration, at which time s-FT₄ was 41.8 ± 15.4 (±SD) pmol/liter (P < 0.001 compared with baseline, 13.6 ± 1.8 pmol/liter), and s-FT₃ was 23.1 ± 9.2 (±SD) pmol/liter (P < 0.001 compared with baseline, 7.0 ± 0.8 pmol/liter). These figures correspond to 204.7 ± 26.1% (±SEM) (FT₄) and 226.9 ± 31.4% (FT₃), respectively, above baseline levels. On d 7 thyroid hormone levels were still elevated [s-FT₄, 20.8 ± 4.9 pmol/liter (P < 0.01); s-FT₃, 9.2 ± 2.4 pmol/liter (P < 0.02)], probably explaining the decrease in serum TSH at this time.

View larger version (19K): [in this window] [in a new window]   FIG. 2. Changes in s-TSH, s-FT4, s-FT3, and s-Tg after administration of 0.9 mg rhTSH (dashed lines) and isotonic saline (solid lines). Values are the mean ± SD (FT4 and FT3) and the median and quartiles (TSH and Tg). TSH and Tg values were logarithmically transformed. In calculating P values, a paired t test was used for FT4 and FT3, and a Wilcoxon test was used for TSH and Tg. *, P < 0.01; **, P < 0.001; ***, P < 0.02 (compared with baseline).

The maximum increase in thyroid volume after rhTSH stimulation did not correlate with the peak level of s-TSH, s-FT₄, s-FT₃, or s-Tg.

Urinary iodine excretion

The 24-h urinary iodine excretion estimated four times during each study period showed huge intraindividual variation. A within-subject fluctuation in iodine excretion by more than 100% was observed in several of the individuals regardless of whether saline or rhTSH was given. After injection of rhTSH or saline, respectively, median urinary iodine excretion during the first 24 h was 173 µg/24 h (range, 141–293 µg/24 h) and 263 µg/24 h (range, 139–477 µg/24 h), respectively (P > 0.05), and was not significantly altered hereafter (data not given).

Adverse effects

In addition to the subject who developed a profound swelling of the thyroid gland, rhTSH caused various adverse effects in the majority of subjects in the early period after injection. Symptoms related to possible thyroid hyperfunction (tachycardia, increased appetite, restlessness, perspiration, headache, nausea and myalgias) were recorded in five individuals after rhTSH compared with one subject after saline. Symptoms related to possible thyroid growth (visual enlargement, thyroid tenderness, or pain) were evident also in five subjects after rhTSH compared with one after saline. In all, seven of nine compared with two of nine had side-effects (P = 0.028, by one-sided ²test) after rhTSH and isotonic saline, respectively. However, the symptoms and discomfort were of short duration and self-limiting, and appeared between 4 and 48 h after rhTSH stimulation. When asked, all subjects were willing to participate in another trial involving rhTSH stimulation.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Whereas previous studies have evaluated the kinetics of rhTSH and its effect on thyroid function (6, 7), the present study is the first to describe in detail the effect on thyroid gland volume. In this randomized, double-blind study, using a precise and accurate ultrasonographic method (18) we have shown that a single injection of 0.9 mg rhTSH results in significant thyroid swelling in healthy subjects. The effect appeared 24 h after injection and peaked at 48 h, with a volume increase of 35% and large interindividual variation. This profound, rapid, and short-lived stimulation, also evidenced by an increase in s-Tg, is most likely due to intravascular and interstitial fluid accumulation, rather than regular growth of the thyroid tissue. Hypoechogenecity and flow-Doppler findings support this. Interestingly, 28 d after rhTSH stimulation thyroid volume was significantly reduced by 14% compared with the baseline. This also explains the small difference between the baseline values in the two study periods. Thus, before saline injection, four of the subjects had been stimulated with rhTSH due to the randomization. The reason for the decreased volume observed at this late point after rhTSH injection is not clear. It may be explained by a reduced trophic stimulus due to the temporary suppression of TSH that ensued after the early and very high peak. Although no subject in our study developed thyroid autoantibodies, long-term follow-up in larger cohorts is necessary to clarify this safety aspect.

As stimulation with rhTSH increases radioiodine uptake in patients with nontoxic goiter (5), it could be speculated that rhTSH can improve the effect of ¹³¹I used for treatment of goiter. Indeed, two recent studies seem to confirm this assumption (8, 9). In the study by Nieuwlaat et al. (9), prestimulation with a very small amount of rhTSH (0.01 or 0.03 mg) in patients with nontoxic nodular goiter (ranging from 44–209 ml) allowed ¹³¹I activity to be halved while still achieving a goiter reduction of approximately 40%. If confirmed in properly conducted randomized studies, attention should focus on safety issues before routine use. In this context our study has important clinical implications. The fact that upper airway obstruction is present in a large fraction of patients with goiter despite the absence of symptoms (21) is often overlooked. Furthermore, ¹³¹I therapy may cause transient goiter enlargement by 15–25% within the first week after ¹³¹I administration (22, 23) (without prior rhTSH stimulation), occasionally leading to severe tracheal compression. Although rarely seen, we have previously reported that serious respiratory problems may complicate ¹³¹I therapy in patients with preexisting tracheal compression (22). The present study points to the possibility that rhTSH stimulation in combination with ¹³¹I therapy may aggravate the above in susceptible individuals. We (22), not using rhTSH prestimulation, and others (9), using rhTSH, have investigated goiter enlargement as well as the smallest tracheal cross-sectional area by magnetic resonance imaging 1 wk after ¹³¹I therapy in benign nodular goiter. On the average, independently of whether rhTSH was used, both structures were insignificantly changed, but a few patients did experience goiter enlargement of up to 17% and a tracheal area reduction of 13%. Accepting that normal thyroid glands may respond differently to rhTSH compared with nodular goiters, it should be kept in mind that the peak enlargement of 35% in the present study appeared 48 h after stimulation, and that the volume after 7 d in fact was below baseline. Thus, it might be possible that a transient, but significant, enlargement of the goiter did, in fact, occur during ¹³¹I therapy (9), but was overlooked. Such an acute enlargement in patients with an intact thyroid gland has actually been reported after stimulation with bovine TSH (10).

Recently, several cases have been reported in which stimulation with 0.9 mg rhTSH caused painful swelling of tumor tissue (11, 12, 13, 14, 15, 16) in patients with papillary thyroid carcinoma. It may not be justified to extrapolate these findings to benign goiter, but our study supports the idea that a similar acute reaction may occur, at least in normal thyroid glands. Moreover, we suggest that side-effects of rhTSH may be more prevalent than hitherto recognized. It is reassuring that rhTSH was well tolerated by all patients with benign goiter in the study by Nieuwlaat et al. (9). However, the number of patients was small (n = 22), and only few had a goiter larger than 150 ml. In view of these considerations, we discourage the indiscriminate use of rhTSH when treating patients with an intact thyroid gland, until further, well designed, controlled studies have been carried out.

Besides the need for a closer evaluation of the acute response after rhTSH in nodular goiters, other issues must be clarified before the use of rhTSH is implemented in the context of benign thyroid disorders. The optimal dose of rhTSH before ¹³¹I therapy has yet to be determined, and it is probably well below 0.9 mg, as indicated by recent studies in nodular goiter as discussed previously (5, 8, 9). Whether such a dose reduction reduces thyroid growth is unclarified. Finally, the reason for rhTSH stimulation occasionally causing profound thyroid swelling needs closer investigation, as does the possibility of preventing this worrisome side-effect with, for example, NSAIDs or corticosteroids.

	Acknowledgments

 
We thank Dr. Peter Laurberg (Department of Endocrinology and Metabolism, Aalborg University Hospital) for the urinary iodine analyses, and Ole Blaaberg (Department of Clinical Chemistry, Odense University Hospital) for supervising the biochemical analyses. Dr. Lars Korsholm (Department of Statistics, University of Southern Denmark) is thanked for valuable advice.

	Footnotes

 
This work was supported by research grants from the Agnes and Knut Mørk Foundation, the Hans Skouby and Emma Skouby Foundation, the Dagmar Marshalls Foundation, the Oda Pedersens Research Foundation, the Frode V. Nyegaard Foundation, the Research Foundation of the County of Funen, the Novo Nordic Foundation, and the A. P. Møller Relief Foundation.

Abbreviations: CV, Coefficient of variation; FT₃, free T₃; FT₄, free T₄; NSAID, nonsteroidal antiinflammatory drug; RAIU, radioiodine uptake; rhTSH, recombinant human TSH; s-, serum level; Tg, thyroglobulin; Tgab, Tg antibody; TPO, thyroid peroxidase; TPOab, thyroid peroxidase antibody; TSH-Rab, TSH receptor antibody.

Received October 10, 2003.

Accepted February 16, 2004.

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