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Original Studies |
Departments of Nuclear Medicine (D.A.H., J.W.B.), Internal Medicine (B.B.), and Clinical Chemistry (A.P.S.), Catharina Hospital, 5602 ZA Eindhoven; Department of Internal Medicine, St. Joseph Hospital (R.J.E.), 5500 MB Veldhoven; and Department of Endocrinology, University Hospital (W.A.N., A.R.H.), 6500 HB Nijmegen, The Netherlands
Address all correspondence and requests for reprints to: Dr. D. Huysmans, Department of Nuclear Medicine, Catharina Hospital, P.O. Box 1350, 5602 ZA Eindhoven, The Netherlands. E-mail: hermus.huysmans{at}freeler.nl
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Abstract |
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After administration of 0.01 mg rhTSH, serum TSH rose from 0.7 ± 0.5 to a peak level of 4.4 ± 1.1 mU/L (P < 0.0001), FT4 rose from 16.0 ± 2.6 to 18.5 ± 3.7 pmol/L (P < 0.0001), and T3 rose from 2.10 ± 0.41 to 2.63 ± 0.66 nmol/L (P < 0.0001). After administration of 0.03 mg rhTSH, TSH rose from 0.6 ± 0.4 to 15.8 ± 2.3 mU/L (P < 0.0001), FT4 rose from 15.2 ± 1.5 to 21.7 ± 2.9 pmol/L (P < 0.0001), and T3 rose from 1.90 ± 0.43 to 3.19 ± 0.61 nmol/L (P < 0.0001). Peak TSH levels were reached at 5–8 h and peak FT4 and T3 levels at 8–96 h after rhTSH administration.
Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30 ± 11% to 42 ± 10% (P < 0.02), 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29 ± 10% to 51 ± 10% (P < 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33 ± 11% to 63 ± 9% (P < 0.0001). After administration of 0.01 mg rhTSH 2 h before 131I, 24-h RAIU did not increase in 1 patient, whereas the increase in 24-h RAIU was less than 10% in 2 other patients. In contrast, administration of rhTSH 24 h before 131I increased 24-h RAIU by more than 10% in all 14 patients (by >20% in 10 and by >30% in 6).
In conclusion, pretreatment with a single, low dose of rhTSH in patients with nontoxic, nodular goiter increased RAIU considerably. Our observations hold promise that administration of rhTSH before 131I therapy for nontoxic, nodular goiter will allow treatment with lower doses of 131I in these patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The amount of radioiodine administered depended on thyroid weight and radioactive iodide uptake (RAIU) in the thyroid in the reported studies. Doses of approximately 100 µCi [3.7 megabecquerels (MBq)] radioiodine/g thyroid tissue corrected for RAIU at 24 h were usually given. As patients with nontoxic, nodular goiter usually have a rather low RAIU, high doses of radioiodine are often needed, causing considerable irradiation of extrathyroidal organs and tissues (9). Therefore, it is of interest to explore strategies to enhance RAIU in these patients.
One of the causes of a low RAIU in patients with nontoxic, nodular goiter is the fact that the serum TSH level is in the low normal range or even below normal in most of these patients. It might be possible to enhance radioiodide uptake in patients with nontoxic, nodular goiter by pretreatment with either bovine TSH or human cadaver TSH. However, bovine TSH is no longer used in humans, because it frequently causes adverse reactions. Human cadaver TSH cannot be used in humans, because of the risk of development of Creutzfeld-Jacob disease.
Recently, recombinant human TSH (rhTSH) has become available for diagnostic use in patients with thyroid cancer. It has been shown that rhTSH stimulates 131I uptake in thyroid remnants that persisted after thyroidectomy and in metastatic thyroid cancer, providing an alternative for thyroid hormone withdrawal for patients undergoing evaluation for thyroid cancer persistence and recurrence (10, 11).
A study in euthyroid mice and rats showed that ip administration of rhTSH (0.1 µg/g BW) given 3 h before administration of radioiodide did not increase RAIU (12). In mice, but not in rats, that were TSH suppressed by prior administration of T3, a significant increase in RAIU was found (12). In two rhesus monkeys, im administration of 0.2 mg rhTSH given 5 h before radioiodide administration increased RAIU (by a factor of 1.85) in only one monkey (13). Administration of 0.2 mg rhTSH on 3 consecutive days in two other monkeys resulted in a doubling of RAIU in both monkeys (13).
To date, no observations have been reported on the influence of rhTSH administration on RAIU in healthy human subjects or patients with benign thyroid diseases. In the present study we investigated whether the administration of a single low dose of rhTSH enhances RAIU in patients with nontoxic, nodular goiter. If so, administration of rhTSH before 131I therapy for nontoxic, nodular goiter holds promise in allowing treatment with lower doses of 131I in these patients.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifteen patients, 14 women and 1 man, aged 61 ± 11 yr (mean ± SD; range, 44–73 yr), referred for radioiodine therapy for volume reduction of nontoxic, nodular goiter, were studied. Four patients were studied twice, and 1 patient was studied 3 times. The mean thyroid weight, as estimated from planar thyroid scintigraphy, was 181 ± 77 g (range, 60–300 g). All patients had normal serum levels of free T4 (FT4; chemiluminescent immunoassay; ACS:180 FrT4, Chiron Corp., Fernwald, Germany; normal values in our laboratory, 9.0–22.3 pmol/L) and total T3 (chemiluminescent immunoassay; ACS T3, Ciba Diagnostics Corp., Medfield MA; normal values in our laboratory, 1.0–3.0 nmol/L), whereas the serum TSH level was normal (n = 12 patients) or below normal (n = 3 patients; two-site chemiluminometric immunoassay; ACS TSH-3, Ciba Diagnostics Corp.; normal values in our laboratory, 0.2–5.5 mU/L). Based on the results of careful palpation of the thyroid followed by fine needle aspiration biopsy of dominant nodules and of those that had a different consistency from other nodules within the gland, there was no suspicion of thyroid cancer in any of the patients. None of the patients had a history of significant cardiopulmonary disease or a recent history of taking any medications known to affect thyroid function or to interfere with hormone measurements or RAIU. None of the patients had received iodine-containing agents in the last 6 months. An electrocardiogram, complete blood count, liver enzyme determinations, plasma creatinine and glucose measurements, and screening urinalysis did not show abnormalities in any of the patients. The study was approved by the institutional human research committee. Written informed consent was obtained from all patients.
Baseline investigations
On the day before radioiodide administration, 24-h urine was collected for measurement of iodide and creatinine excretion. Iodide excretion was 163 ± 46 µg/24 h (range, 102–273 µg/24 h). Immediately before radioiodide administration, blood was drawn for measurements of serum FT4, T3, and TSH. A diagnostic dose of 20 µCi (0.8 MBq) sodium (131I) iodide was administered as an oral solution [together with 1 mCi (40 MBq) sodium (123I) iodide for thyroid scintigraphy]. RAIU as a percentage of the administered dose of 131I, corrected for physical decay, was measured at 3, 6, 24, 48, 72, and 168 h, using a 3 x 3-in. NaI(Tl) detector. Deadtime corrections were made using standard software. The use of the net area under the 364-keV peak of 131I was checked to prohibit any interference of the low energy photons of 123I with RAIU measurements. Thyroid scintigraphy in the 159-keV window of 123I was performed 24 h after radioiodide administration (results not included in the present report).
Investigations with rhTSH
The influence of rhTSH on thyroid hormone levels and RAIU was investigated in each patient at least 2 weeks after radioiodide administration for the baseline investigations. On the day before the administration of rhTSH, 24-h urine was collected for measurements of iodide and creatinine excretion. Iodide excretion was 177 ± 48 µg/24 h (range, 112–265 µg/24 h). Immediately before the administration of rhTSH, blood was drawn for measurement of serum FT4, T3, and TSH. After reconstitution of freeze-dried rhTSH (ampoules containing 0.9 mg rhTSH; Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) with 1.2 mL sterile water, part of the obtained solution was diluted with saline to a final concentration of 0.05 mg/mL. Immediately after dilution, 0.01 mg (0.2 mL; n = 14) or 0.03 mg (0.6 mL; n = 7) rhTSH was injected im in the quadriceps muscle. Vital signs (blood pressure, pulse rate, and body temperature) were recorded, and blood was drawn for measurement of serum FT4, T3, and TSH 2, 5, 8, 24, 48, 72, 96, and 192 h after administration of rhTSH. A diagnostic dose of 20–40 µCi (0.8–1.6 MBq) sodium 131I was administered as an oral solution [together with 1 mCi (40 MBq) sodium 123I for thyroid scintigraphy] either 2 h after the administration of rhTSH (0.01 mg; n = 7) or 24 h after the administration of rhTSH [0.01 mg (n = 7) or 0.03 mg (n = 7)]. RAIU as a percentage of the administered dose of 131I, corrected for background activity from the radioiodine from the baseline investigation and for physical decay, was measured at 3, 6, 24, 48, 72, and 168 h. Thyroid scintigraphy was performed 24 h after radioiodide administration (results not included in the present report).
Statistical analyses
The mean ± SD are given. Statistical analyses were performed using the Mann-Whitney U test for unpaired observations (P values denoted as P), the Wilcoxon sign-rank test for paired observations (P values denoted as P1), and the Spearman rank correlation test (P values denoted as P**). The level of significance was 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Effect of rhTSH administration on serum TSH, FT4, and T3 levels
After 0.01 mg rhTSH, serum TSH rose from 0.7 ± 0.5 mU/L
(range, <0.03 to 1.7 mU/L) to a peak of 4.4 ± 1.1 mU/L (range,
2.2–6.3 mU/L; P1 < 0.0001). After 0.03 mg rhTSH, TSH rose
from 0.6 ± 0.4 mU/L (range, < 0.03–1.2 mU/L) to a peak of
15.8 ± 2.3 mU/L (range, 13.6–20.0 mU/L; P1 <
0.0001). Peak TSH levels were reached at 5–8 h after administration of
either dose of rhTSH (Fig. 1
).
Thereafter, TSH declined rapidly, and in all patients a transient
decrease in serum TSH below the baseline level was observed. One week
after rhTSH administration, TSH levels did not differ significantly
from baseline levels in both groups of patients.
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Effect of rhTSH administration on RAIU (Table 1)
Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30 ± 11% to 42 ± 10% (P1 < 0.02); 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29 ± 10% to 51 ± 10% (P1 < 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33 ± 11% to 63 ± 9% (P1 < 0.0001).
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The ratio between 24-h RAIU after rhTSH and baseline 24-h RAIU showed a significant inverse correlation with baseline 24-h RAIU (r = -0.79; P** < 0.04 for patients who received 0.01 mg rhTSH 2 or 24 h before radioiodide and r = -0.89; P** < 0.007 for patients who received 0.03 mg rhTSH). The ratio between 24-h RAIU after rhTSH and baseline 24-h RAIU was not significantly correlated with the baseline TSH level.
The biological half-time of radioiodine in the thyroid, as estimated from the RAIU values of time points 48–168 h after the administration of radioiodide, was 61.3 ± 27.3 days in the baseline investigation and 56.6 ± 31.4 days in the investigation after rhTSH (P1 = NS).
Baseline 24-h RAIU and 24-h RAIU after rhTSH in individual patients are
shown (Fig. 2). Of note, after
administration of 0.01 mg rhTSH 2 h before
131I, 24-h RAIU did not increase in 1 patient,
whereas the increase in 24-h RAIU was less than 10% in 2 other
patients. In contrast, administration of rhTSH 24 h before
131I increased 24-h RAIU by more than 10% in all
14 patients (by >20% in 10 and by >30% in 6).
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). The ratio between
24-h RAIU after rhTSH and baseline 24-h RAIU was significantly higher
for the 24-h interval between rhTSH and radioiodide administration than
for the 2-h interval (P1 < 0.0001).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The doubling of RAIU was reached by the use of remarkably low doses of rhTSH (0.01 or 0.03 mg). For comparison, a single im injection of 0.1 mg rhTSH was used in a study of the effects of rhTSH on serum thyroid hormone levels in six normal volunteers (14), whereas im injections of 0.9 mg rhTSH were used in two phase 3 studies in patients with thyroid cancer (10, 11). Accordingly, we found considerably lower peak levels of TSH (4.4 ± 1.1 mU/L after 0.01 mg rhTSH and 15.8 ± 2.3 mU/L after 0.03 mg rhTSH) than observed in normal volunteers after 0.1 mg rhTSH (50.9 ± 22.8 mU/L) (14) and in thyroid cancer patients after 0.9 mg rhTSH (101 ± 60 mU/L) (10).
In our study, the interval between the administration of rhTSH and radioiodide appeared to be an important factor for increasing RAIU; a 24-h interval between rhTSH administration and radioiodide administration was significantly more effective than a 2-hinterval. This finding is in accordance with the results of in vitro studies using FRTL-5 cells (15, 16). Weiss et al. (15) demonstrated that 12–24 h were needed for the onset of stimulation of iodide transport by a purified preparation of TSH. Kogai et al. (16) demonstrated that rhTSH (1 mU/mL) increased iodide-125 uptake only after 12 h of incubation, reaching a maximum after an incubation period of 72 h.
Iodide uptake across the basolateral membrane of thyroid follicular cells is catalyzed by the Na+/I- symporter (NIS). Immunohistochemical studies have demonstrated that under normal conditions, there is only limited expression of the Na+/I- symporter in the plasma membrane of thyroid follicular cells (17, 18). Kogai et al. (16) have shown that in FRTL-5 cells rhTSH induces a significant increase in NIS messenger ribonucleic acid at 3–6 h, reaching a maximum at 24 h. NIS protein levels were significantly increased only after 36 h, reaching a maximum at 72 h. Thus, optimal expression and/or activation of the Na+/I- symporter may take some time, which might explain our observation that a 24-h interval between rhTSH administration and radioiodide administration was significantly more effective in increasing RAIU than a 2-h interval.
We found that the effects of administration of 0.03 and 0.01 mg rhTSH on RAIU were not significantly different. In contrast, 0.03 mg rhTSH caused a significantly greater maximal increase in serum thyroid hormone levels (42% increase in FT4, 69% increase in T3) than did 0.01 mg rhTSH (15% increase in FT4, 25% increase in T3). In only 8 of 21 observations was serum FT4 and/or T3 increased beyond the normal range after rhTSH administration, and in none of the patients were symptoms or signs of thyrotoxicosis (or any other side-effect) observed. For comparison, the increases in serum thyroid hormone levels after either dose of rhTSH appeared to be less than those found in normal volunteers after the administration of 0.1 mg rhTSH (54% increase in total T4 and 89% increase in total T3) (14).
No adverse effects of the administration of a single low dose of rhTSH were observed in our study. However, before rhTSH can be advised as an adjunct to radioiodine therapy in patients with nontoxic, nodular goiter, the safety of the administration of a therapeutic dose of radioiodine after pretreatment with rhTSH has to be investigated thoroughly. First, it has to be determined that pretreatment with rhTSH does not exacerbate the mild increases in serum thyroid hormone levels and thyroid volume commonly seen after radioiodine treatment of nontoxic, nodular goiter (19). Second, it has to be shown that administration of rhTSH before radioiodine therapy does not induce a rapid release of 131I-labeled thyroid hormones and/or thyroglobulin from the thyroid into the circulation, thereby increasing total body irradiation.
Our observations hold promise for rhTSH as an adjunct to radioiodine treatment for thyroid volume reduction in patients with nontoxic, nodular goiter, as it may allow treatment with lower doses of 131I. Furthermore, the administration of rhTSH may alter the distribution of radioiodine within the thyroid gland, which may be particularly advantageous if it enhances the uptake of radioiodide in cold areas. Our study was performed in an area with borderline sufficient iodine intake. The effect of rhTSH pretreatment on RAIU may be even greater in areas with a higher iodine intake. However, randomized studies comparing the efficacies of radioiodine therapies with and without rhTSH pretreatment need to be performed before its use can be advised.
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Footnotes |
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Received April 4, 2000.
Revised June 23, 2000.
Accepted June 29, 2000.
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) and 24-h
radioactive iodide uptake after administration of recombinant human TSH
(
) in 15 patients with nontoxic, nodular goiter. Patients are
identified at the bottom of the figure as a to o. Four
patients (a, d, e, and f) were studied twice; one patient (g) was
studied 3 times. Serum TSH levels (milliunits per L) immediately before
administration of rhTSH are also given at the bottom of
the figure.
, Baseline 24-h radioactive iodide uptake;