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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2836-2839
Copyright © 1997 by The Endocrine Society

Original Studies

Recombinant Human Thyrotropin Is a Potent Stimulator of Thyroid Function in Normal Subjects1

Luis Ramirez, Lewis E. Braverman, Bernadette White and Charles H. Emerson

Department of Medicine, Division of Endocrinology and Metabolism, University of Massachusetts School of Medicine, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Charles H. Emerson, M.D., University of Massachusetts School of Medicine, Worcester, Massachusetts 01655.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Recombinant human TSH (rhTSH) is known to stimulate 131I uptake and thyroglobulin (Tg) release from the postoperative remnant and metastases in thyroid cancer patients, but its effects on serum thyroid hormone and Tg concentrations in normal subjects have not been reported. Before using rhTSH in the management of thyroid disorders other than cancer, the thyroid response to rhTSH in normal subjects must be assessed. Six subjects, two men and four women, without evidence of thyroid disease, including normal serum free T4 index and TSH concentrations and negative tests for antithyroid peroxidase and Tg, were studied. Each received 0.1 mg rhTSH, im, 11% of the lowest dose that has been administered to thyroid cancer patients. Blood was obtained before; 2, 4, and 8 h after; and 1, 2, 3, 4, 7, and about 3 weeks after rhTSH administration. Serum TSH significantly increased at 2 h (mean ± SE, 2.4 ± 0.9 to 40.7 ± 7.4 mU/mL), peaked at 4 h (50.9 ± 9.3), remained significantly elevated for 1 day, and was significantly below baseline (0.8 ± 0.5) 7 days after rhTSH administration. Serum T3 increased significantly at 4 h (115 ± 4 to 190 ± 14 ng/dL), peaked at 24 h (217 ± 23 ng/dL), and remained significantly elevated for 3 days (151 ± 12 ng/dL). Serum T4 increased significantly at 8 h (7.3 ± 0.2 to 9.8 ± 0.4 µg/dL), peaked at 24 h (11.2 ± 0.5 µg/dL), and remained significantly elevated for 4 days (9.4 ± 0.5 µg/dL). Serum Tg did not change for the first 8 h, increased significantly at 1 day (15.9 ± 3.9 to 34.7 ± 6.0 ng/mL), peaked at 2 days (44.2 ± 7.0 ng/mL), and remained significantly elevated for 4 days (37.7 ± 13.7 ng/mL). All values returned to baseline at 3 weeks. TSH antibodies were not detected at 3 weeks. A single dose of 0.1 mg rhTSH is a potent stimulator of thyroid function in normal subjects. rhTSH may be a useful agent to test thyroid reserve and for use in clinical settings that require direct thyroid stimulation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TSH, A SPECIFIC and potent thyroid stimulator, is essential for normal thyroid function. Early studies documented that bovine TSH (bTSH) administration actively stimulated an increase in the serum protein-bound iodine in normal volunteers (1, 2). Later similar findings with bTSH were reported for serum T4, T3, and thyroglobulin (Tg) concentrations (3, 4, 5, 6). Due to its availability, bTSH was used in research protocols and in clinical practice to test thyroid reserve, in the management of thyroid cancer to stimulate 131I uptake after near-total thyroidectomy, to improve the quality and interpretation of thyroid nuclear medicine tests, and as an aid in the differential diagnosis of hypothyroidism (7, 8, 9, 10, 11). Its use eventually became limited, however, because of adverse reactions, including nausea, vomiting, local induration, urticaria, and even anaphylaxis (2, 12, 13). Moreover, neutralizing antibodies to human TSH developed in some patients who were treated with bTSH, causing interference in TSH assays (14) and adversely affecting thyroid function (15). Therefore, bTSH is no longer being produced for human use. Human cadaver TSH is also a good thyroid-stimulating agent (16, 17), but its scarcity and the risk that it will be associated with the development of Crutzfield-Jacob disease years later (18) precludes its clinical use.

Recently, recombinant human TSH (rhTSH) was synthesized and made available for phase II and III clinical research protocols in patients with thyroid cancer. These studies have focused on the potential for rhTSH to stimulate 131I uptake in thyroid remnants that persisted after thyroidectomy or in metastatic thyroid cancer (19). The ability of rhTSH to stimulate the secretion of thyroid hormones could not be evaluated in these studies because in all patients thyroid function was compromised by surgery, and in some it was compromised by 131I therapy. However, the ability of rhTSH to stimulate Tg release from remnant normal or malignant thyroid tissue in humans and T4 and T3 from normal primate thyroids has been documented (19, 20). We now describe the first studies of the effects of rhTSH administration on thyroid hormone and Tg secretion in normal euthyroid subjects as a first step in evaluating its use in patients with nonmalignant thyroid disease or in those exposed to pharmacological doses of iodine.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Men and women, aged 21–55 yr, were invited to participate in this study if they had no history of thyroid disease. A history, physical examination, electrocardiogram, urinalysis, complete blood count (CBC), chemistry profile, thyroid function tests, and urinary iodine measurements were carried out in all subjects before their inclusion in the study. Thyroid function tests were performed for serum T4, free T4 index (FTI), T3, TSH, Tg, and thyroid peroxidase (TPO) and Tg antibody concentrations. The chemistry profile consisted of serum creatinine, alkaline phosphatase, serum glutamic oxaloacetic transaminase, and glucose concentrations. A urine pregnancy test was obtained in all women.

Candidates were accepted into the study if they did not have any evidence of thyroid disease. An abnormal thyroid on physical examination; signs of Graves’ ophthalmopathy, a history of thyroid disease; or abnormal values for serum FTI, T3, TSH, or Tg or for Tg and/or TPO antibodies excluded subjects from the study. Other important exclusion criteria were evidence of a serious or moderately severe medical problem, pregnancy, a history of substance abuse, or a history of taking any medications known to affect thyroid function or interfere with hormone measurements. The participants in the study consisted of two men and four women, ranging in age from 24–55 yr. Information concerning age, sex, and medication is presented in Table 1Go.


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  		Table 1. Characteristics of the subjects receiving rhTSH

 
After qualifying for the study, a 24-h urine sample for measurement of iodine and creatinine concentrations was collected. The following day (day 0) the rhTSH administration protocol was carried out. After baseline blood samples were obtained through an indwelling catheter placed in an anticubital vein, 0.1 mg lyophilized rhTSH was reconstituted in 1 mL sterile water and administered im into a deltoid muscle. Blood was obtained for analysis 2, 4, 8, and 24 h after rhTSH administration. Additional blood samples were obtained at 2, 3, and 4 days and at 1 and 3 weeks. Serum FTI, T4, T3, TSH, and Tg concentrations were measured in all blood samples. A CBC and chemistry profile was performed in blood obtained immediately before rhTSH administration, and blood obtained before and 3 weeks after rhTSH administration was tested for anti-TSH antibodies. rhTSH was provided by Genzyme Corp. (Cambridge, MA) and was supplied as Thyrogen. Blood was obtained 2, 4, and 8 h after rhTSH administration through the indwelling catheter and by venipuncture at 1, 2, 3, 4, and 7 days. A final morning blood sample was obtained 3–4 wk after rhTSH administration. All sera were kept frozen at -20 C until assayed for thyroid parameters. The protocol was approved by the committee for the protection of human subjects in research, University of Massachusetts Medical Center, and written informed consent was obtained from each participant.

Serum T4, FTI, T3, and TSH concentrations were measured using the Ciba Corning Automated Chemiluminescence System (Ciba Corning Diagnostic Corp., Medfield, MA). Serum Tg concentrations and Tg and TPO antibodies were measured using Kronus kits (Kronus Corp., San Clemente, CA). All measurements were performed in duplicate, and all samples from a given subject were performed in the same assay. Urinary iodide concentrations were measured by the ceric-arsenic redox reaction (21). The test for anti-TSH antibodies was performed by Genzyme Corp., using an enzyme-linked immunosorbent assay.

The data were analyzed by ANOVA followed by Dunnett’s multiple comparison procedure. Log transformation of the data was performed when there were significant differences in the SDs, as was the case for the serum TSH and Tg data. Significance was established at the 95% confidence level. The results of serum T3, T4, and FTI determinations before and after rhTSH administration were also analyzed by paired Student’s t test; the justification for this approach was that rhTSH has been shown to stimulate the secretion of T4 and T3 in rhesus monkeys (20) and the observation that administration of other TSH preparations, such as bovine and cadaver human TSH, cause an increase in serum T4 and T3 in humans. Unless otherwise stated, the results are presented as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Urinary iodide excretion in subjects was normal and ranged from 101–426 µg/day. Serum TSH, T4, FTI, T3, and Tg concentrations before and after rhTSH administration are presented in Table 2Go. Two hours after rhTSH administration, serum TSH concentrations increased from 2.4 ± 0.9 to 40.7 ± 7.4 µU/mL. Serum TSH concentrations then remained markedly elevated for 24 h. Seven days after rhTSH administration, mean serum TSH concentrations were significantly lower than those before rhTSH administration, with individual values ranging from 0.08–3.06 µU/mL. Four of six subjects had serum TSH values below the normal range, although not as low as those in clinically thyrotoxic patients or in patients with thyroid cancer who are being treated with TSH-suppressing doses of L-T4. Serum TSH concentrations 21–28 days after rhTSH administration were similar to those before rhTSH administration.


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  		Table 2. Serum FTI, T4, T3, thyroglobulin, and TSH after rhTSH administration

 
Mean serum T4, FTI, and T3 concentrations were higher 2 h after rhTSH administration and increased progressively thereafter (Table 2Go). By ANOVA, the increases in serum T3 concentrations were significant at 4 h, and those in serum T4 and FTI concentrations were significant at 8 h. By paired Student’s t test, there was a significant increase in serum T3, T4, and FTI 2 h after rhTSH administration. For at least the first 24 h after rhTSH administration, there was a progressive rise in serum T4, FTI, and T3. Overall, the maximum increase in the mean serum T4 concentration was 54%, and the maximum increase in the mean serum T3 concentration was 89% (Fig. 1Go).



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  		Figure 1. Serum T4, T3, and Tg concentrations before and after sc administration of 0.1 mg rhTSH in normal subjects. Significant differences (P < 0.05) between the mean values before and the mean values after rhTSH administration, as determined by ANOVA followed by Dunnett’s multiple comparison procedure, are indicated by asterisks. Analysis of the data by Student’s paired t test indicated significant increases in serum T3 and T4 2 h after rhTSH administration.

 
The highest serum T4 concentrations and FTI values were noted 1 and 2 days after rhTSH administration; the values were almost identical at these times. In the case of T3, the highest values were also noted 1 day after rhTSH administration, but at 8 h, mean serum T3 concentrations were almost as high as those present at 1 day. By 2 days after rhTSH administration, mean serum T3 values had declined to slightly less than those at 8 h. Serum T4 and T3 concentrations remained significantly elevated for as long as 4 and 3 days, respectively, after rhTSH was administered and were similar to baseline values thereafter.

There was little change in serum Tg concentrations for at least 8 h after rhTSH administration (Table 2Go). One day after rhTSH administration, however, serum Tg concentrations were more than 2-fold higher than those at baseline (Fig. 1Go). The mean serum Tg concentrations were slightly higher at 2 days and then declined; they remained significantly elevated for at least 4 days after rhTSH administration and were similar to baseline thereafter.

Except for mild soreness at the injection site, all subjects tolerated rhTSH administration well. The CBC, serum creatinine, alkaline phosphatase, serum glutamic oxaloacetic transaminase, and glucose concentrations were similar before and 1 week after rhTSH administration. Antibodies to TSH were not detected in any subject before or 3 weeks after rhTSH administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results indicate that a single injection of a relatively small dose of rhTSH is a potent stimulus of T4, T3, and Tg secretion in normal subjects. Similar to previously reported results with bTSH administration (3, 4, 5, 6), serum T3 concentrations rose slightly earlier than serum T4 concentrations, and the rise in serum Tg was delayed until approximately 24 h. The decrease in serum TSH values 7 days after rhTSH administration is almost certainly due to the rhTSH-induced increases in serum T4 and T3 concentrations. The relative degree to which T4, T3, and Tg rose was also similar to that reported for bTSH (6), with the incremental increase in Tg being greater than that in either T3 or T4, and the increase in serum T3 being slightly greater than that in T4. Unlike the experience with bTSH, allergic reactions and anti-TSH antibody formation were not noted after rhTSH administration.

Just as rhTSH shows promise for treatment of patients with thyroid cancer (19, 22, 23), the present results indicate that it may be feasible to use rhTSH in thyroid conditions unrelated to cancer. In the past, bTSH was employed in conjunction with the thyroid radioactive iodine (RAI) uptake (RAIU) test and the serum protein-bound iodine determination to differentiate between primary and secondary hypothyroidism. Testing with bTSH began to decline not only because of reports of adverse reactions to bTSH, but also because it was thought that serum TSH measurements would clearly differentiate between primary hypothyroidism and hypothyroidism secondary to pituitary or hypothalamic dysfunction. It is now apparent, however, that some patients with central hypothyroidism secrete TSH with reduced bioactivity (24). Their serum TSH concentrations are not low and may even be mildly elevated (25), suggesting the diagnosis of primary hypothyroidism. In such patients, the thyroid response to rhTSH should help to distinguish between primary and secondary hypothyroidism or establish the presence of disease in both the pituitary and thyroid.

When rhTSH becomes available, another potential use might be to confirm the diagnosis of primary hypothyroidism in patients who are taking thyroid hormone for reasons that are unclear. Some patients present with a history of thyroid hormone treatment for many years, but without laboratory or clinical records that substantiate hypothyroidism. At times, the original indication for starting thyroid hormone was one that is no longer considered valid (26). A possible method for substantiating the diagnosis of hypothyroidism in patients receiving thyroid hormone without requiring that they discontinue their medication would be to test thyroid reserve by administering rhTSH. Early findings that the thyroid response to bTSH is not affected by the concomitant administration of thyroid hormone (1) provide a rationale to use the thyroid response to rhTSH as a means of determining whether primary hypothyroidism exists in thyroid hormone-treated patients.

The so-called sick euthyroid syndrome is a common entity whose pathogenesis is complex and multifactorial. There is evidence for central inhibition of the hypothalamic-pituitary-thyroid axis as well as peripheral changes in thyroid hormone binding, cellular uptake, and metabolism (27). Most importantly, studies in animal models and cell culture suggest that the effects of TSH on the thyroid may be blunted in the sick euthyroid syndrome (28, 29, 30, 31). Using rhTSH, it should be possible to determine whether patients with the sick euthyroid syndrome are universally insensitive to TSH or whether there is a subset of patients with this problem.

rhTSH might also be useful in conjunction with RAI treatment of toxic multinodular goiter or in euthyroid patients with large goiters to reduce their size and alleviate symptoms of compression (32, 33). A limitation in the treatment of both toxic and nontoxic multinodular goiter is that some patients have a relatively low RAIU. In these patients, administration of rhTSH before RAI treatment might result in more reliable ablation of autonomous thyroid function, decreased incidence of recurrent thyrotoxicosis, and a greater reduction in thyroid size. Prior treatment with antithyroid drugs to decrease thyroid stores of T4 and T3 might be necessary.

Finally, iodide exposure from iodine-containing medications such as amiodarone, nature foods such as kelp, or iodine-rich x-ray contrast agents is a problem in the management of thyroid diseases. It can interfere with thyroid RAIU tests and scans (34) and precipitate thyrotoxicosis in nontoxic patients (35) or exacerbate underlying thyrotoxicosis in patients with toxic multinodular goiter. In these thyrotoxic patients, RAI treatment is ineffective because of the markedly low RAIU. As some experimental studies suggest that TSH can increase thyroidal iodide uptake and/or organification in the presence of relatively high amounts of iodide (36, 37), it is possible that administration of rhTSH could be used to obtain satisfactory RAIU tests and scans or facilitate RAI treatment of thyrotoxicosis in iodine-loaded patients.

In summary, a single injection of rhTSH is a potent stimulus to thyroid hormone and Tg secretion in normal subjects. It is not associated with allergic reactions or the generation of anti-TSH antibodies. rhTSH, therefore, is likely to become the most suitable agent in clinical practice for testing thyroid reserve and augmenting thyroid function.


   Footnotes
 
1 This work was supported in part by Grant DK-18919 from the NIH (Bethesda, MD). Back

Received April 7, 1997.

Revised May 20, 1997.

Accepted May 30, 1997.


   References
Top
 Abstract
 Introduction
 Subjects 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