The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 211-214
Copyright © 2003 by The Endocrine Society
Cardiovascular Safety of Acute Recombinant Human Thyrotropin Administration to Patients Monitored for Differentiated Thyroid Cancer
Bernadette Biondi,
Emiliano A. Palmieri,
Loredana Pagano,
Michele Klain,
Giovanna Scherillo,
Marco Salvatore,
Gianfranco Fenzi,
Gaetano Lombardi and
Serafino Fazio
Department of Clinical and Molecular Endocrinology and Oncology (B.B., L.P., G.F., G.L.), Department of Clinical Medicine and Cardiovascular Sciences (E.A.P., G.S., S.F.), Department of Biomorphological and Functional Sciences (M.K., M.S.), University of Naples Federico II School of Medicine, 80131 Naples, Italy
Address all correspondence and requests for reprints to: Bernadette Biondi, M.D., Department of Clinical and Molecular Endocrinology and Oncology, via S. Pansini 5, 80131 Naples, Italy. E-mail: bebiondi{at}libero.it.
 |
Abstract
|
|---|
Eleven patients who had undergone total thyroidectomy for differentiated thyroid cancer and who were on chronic TSH-suppressive therapy with levothyroxine (L-T4), underwent 24-h Holter electrocardiogram and Doppler-echocardiography before and after acute recombinant human TSH (rhTSH) administration for disease staging. The treatment, which was generally well tolerated, did not affect circulating thyroid hormones levels, nor did it have measurable effects on heart rate, rhythm, left ventricular morphology, or systo-diastolic function. Notably, arterial blood pressure tended to be slightly reduced after rhTSH administration, although in no instance did the patients become frankly symptomatic. Our data demonstrate that rhTSH does not alter cardiovascular function acutely. Consequently, it can safely be used in the routine staging of patients affected by differentiated thyroid cancer.
|
Introduction
|
|---|
CHRONIC TSH-SUPPRESSIVE therapy with levo-thyroxine (L-T4) prevents recurrences in the postsurgical management of patients with differentiated thyroid cancer (1, 2, 3, 4). However, this treatment must be periodically withdrawn for short periods to allow disease staging by radioiodine whole-body scanning and serum thyroglobulin measurement (5, 6). Withdrawal of L-T4 treatment leads to acute hypothyroidism, which can be hazardous in patients with underlying cardiovascular disorders, especially in the elderly (7, 8, 9, 10, 11, 12). Ever since it became commercially available, recombinant human TSH (rhTSH) has been proposed as an alternative to L-T4 withdrawal in the staging of patients with differentiated thyroid cancer (13, 14, 15, 16). Indeed, the recent and controversial evidence that the membrane-bound TSH receptor might be expressed in the mammalian heart, including human heart (17, 18, 19, 20), raised the question as to whether the marked increase in circulating TSH concentration after rhTSH administration could have clinically relevant cardiovascular effects in these patients.
To address this question, we have used 24-h Holter electrocardiogram (ECG) and Doppler-echocardiography to evaluate the cardiovascular safety of acute rhTSH administration to patients monitored for differentiated thyroid cancer.
|
Materials and Methods
|
|---|
The study was performed in 11 patients [7 females, 4 males; mean age (±SD): 48 ± 9 yr] who had undergone total thyroidectomy for differentiated thyroid cancer (7 papillary and 4 follicular thyroid carcinomas) and at least one course of radioiodine therapy. All patients were on chronic TSH-suppressive therapy with L-T4 (mean [±SD] weekly L-T4 dose: 1,058 ± 215.1 µg; treatment duration ranging from 1–17 yr; TSH: 0.2 ± 0.1 mU/liter; F-T4: 16.8 ± 2.8 pmol/liter; F-T3: 7.1 ± 1.3 pmol/liter); two patients were on a ß-blocker (bisoprolol: 5 mg/d) because of recurrent episodes of atrial fibrillation during L-T4 therapy; three patients were on antihypertensive therapy; and one was on nitrates because of coronary artery disease. Written informed consent was obtained from each patient, and the study was approved by the Ethics Committee of the University of Naples Federico II.
rhTSH (Thyrogen, TSH 
; Genzyme Corp., Bologna, Italy) was administered by means of two im injections, at a dose of 0.9 mg each, on a consecutive 2 d, according to clinical trials on the diagnostic use of rhTSH in the follow-up of differentiated thyroid cancer (13, 14, 15, 16). Patients underwent 24-h Holter ECG 1 wk before and during the 24 h after the second rhTSH injection, and Doppler-echocardiography 1 wk before and 24 h after the second rhTSH injection. Twenty-four-hour Holter ECG and Doppler-echocardiography were performed as reported elsewhere (21, 22). Serum TSH and thyroid hormones were measured at baseline, and 48 and 72 h after the second injection of rhTSH. Individual medical therapy was left unchanged throughout the study.
Data are reported as the mean ± SD; the two-tailed Student’s t test was used for comparisons. A P value less than 0.05 was considered statistically significant.
|
Results
|
|---|
No patient complained of clinically relevant adverse effects during rhTSH administration, except for a mild headache in four patients (36%). Serum TSH concentration remarkably increased in all patients after rhTSH administration (P < 0.001 vs. baseline), whereas the levels of circulating thyroid hormones remained unchanged (Fig. 1
). Compared with baseline, there were no significant variations in average heart rate (81 ± 10 vs. 79 ± 10, P = 0.748), 24-h heart rate trend, and prevalence of atrial and/or ventricular premature beats after rhTSH (Table 1 and Fig. 2). Doppler-echocardiography showed no significant change in left ventricular morphology and systo-diastolic function, as indicated by comparable pre- and post-rhTSH values of left ventricular dimension and wall thickness, mean aortic acceleration, and isovolumic relaxation time (Table 2). Notably, systolic and diastolic blood pressures tended to be slightly lower after rhTSH administration, although the difference was not significant (systolic arterial pressure: 125 ± 12 vs. 120 ± 11, P = 0.077; diastolic arterial pressure: 83 ± 12 vs. 78 ± 9, P = 0.053). However, in no instance did the decrease in systemic arterial pressure became frankly symptomatic. No difference in the above cardiovascular parameters was detected when the patients were grouped and analyzed taking into account the presence of concomitant cardiovascular treatment (6 patients receiving cardiovascular medications vs. 5 patients without cardiovascular treatment, all P = NS; data not shown).
View larger version (16K):
[in this window]
[in a new window]
|
Figure 1. Serum TSH and thyroid hormones profiles after rhTSH administration. Reference ranges in our laboratory are: TSH, 0.3–3.8 mU/liter; free T4, 7.7–20.6 pmol/liter; free T3, 4.0–9.2 pmol/liter; *, P < 0.001 vs. baseline.
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Figure 2. Average heart rate and 24-h heart rate trend at baseline and after rhTSH administration. HR, Heart rate.
|
|
|
Discussion
|
|---|
Short-term withdrawal of L-T4 therapy is mandatory for accurate staging of patients with differentiated thyroid cancer by whole-body scan assessment and serum thyroglobulin measurement. However, it is associated with the development of acute cardiovascular hypothyroidism (7, 8, 9, 10, 11, 12), which can be life-threatening in patients with underlying cardiovascular disorders, especially in the elderly. Therefore, rhTSH, now commercially available, has been proposed as an alternative to hormone withdrawal (13, 14, 15, 16). However, its cardiovascular safety has not been systematically investigated.
Our data demonstrate, for the first time, that acute rhTSH administration in the follow-up of differentiated thyroid cancer is clinically safe and is not accompanied by relevant cardiovascular adverse effects. None of our patients reported significant adverse effects after the increase in serum TSH levels; 24-h Holter ECG did not reveal any change in heart rate or in the prevalence of arrhythmias; and Doppler-echocardiography did not show any change in left ventricular morphology and function. Indeed, rhTSH administration was accompanied by a slight reduction in arterial blood pressure, although in no instance did the patients became clinically symptomatic.
Interrelations between TSH and the cardiovascular system have attracted increasing attention since 1995, when Drvota and colleagues (17) identified mRNA encoding the membrane-bound TSH receptor in human heart and demonstrated that TSH stimulation of cultured mouse cardiomyocytes resulted in a significant increase in the levels of intracellular second messenger cAMP, thus suggesting that the TSH receptor plays a functional role in human heart. Support for this hypothesis came from Kashiyama and co-workers (18), who, in 1996, identified the TSH receptor mRNA in the myocardial biopsies of a 25-yr-old man affected by cardiomyopathy and severe heart failure, before developing clinically overt Graves’ disease. Because pathological examination of the myocardial specimens showed fibroblast infiltration and degenerative changes, it was suggested that autoimmunity against the TSH receptor might have contributed to the cardiomyopathy. Based on the above evidence, in 1997 Sellitti et al. (19) examined the regional distribution of TSH receptor mRNA in pig heart to map the potential cardiac sites of TSH action. They found that TSH receptor mRNA expression in porcine heart varied regionally (coronary arteries, epicardial fat > right atrium > left atrium > right ventricle, aorta > left ventricle, ventricular cardiomyocytes), thus suggesting that areas of highest expression might be sites where the TSH receptor exerts a biological role. More recently, however, Busuttil and Frauman (20) failed to detect TSH receptor mRNA in the myocardium of any chamber of the normal human heart (20). This result could reflect the scarcity of TSH receptor in cardiac muscle per se, and thus highlight the methodological difficulties inherent in detecting minute amounts of mRNA (23).
In this controversial framework, our finding that acute rhTSH administration had no short-term adverse effect suggests that, if actually expressed, the TSH receptor would play a marginal role in cardiac physiology. However, it cannot be excluded that TSH may became pathophysiologically relevant when chronically increased. On the other hand, our patients were on chronic TSH-suppressive therapy with L-T4, which might have down-regulated or desensitized the TSH receptor in the heart. Interestingly, Nagayama and colleagues (24) have recently found that the G protein-coupled receptor kinase-5, which is involved in the homologous desensitization of the TSH receptor in the thyroid, is also expressed in the heart. However, whether the kinase activity can be modulated by thyroid hormone is unknown.
An intriguing observation in our study is that rhTSH administration was accompanied by a slight reduction in arterial blood pressure. Although the magnitude of this effect did not reach significance (most probably because of the small number of patients), the finding suggests that the increase in circulating TSH could lead to a mild vasodilatory effect. Interestingly, there is a significant dose-dependent increase in intracellular cAMP in cultured human coronary artery smooth muscle cells upon exposure to TSH (25). Therefore, given the role that cAMP plays in the regulation of vascular tone (26), it is a tempting to speculate that TSH might be involved in vascular physiology.
A possible limitation in the present study is that almost half of our patients were receiving cardiovascular medications, which might have interfered with rhTSH action. However, although the number of patients investigated was limited, we did not observe differences between patients with ongoing cardiovascular treatment and those without.
In conclusion, acute rhTSH administration to patients monitored for differentiated thyroid cancer is safe and is not associated with cardiovascular adverse effects, thus reinforcing its routine use as an alternative to L-T4 withdrawal. In addition, the present study might serve the heuristic purpose of focusing future research on the role of TSH in vascular physiology, which would be of considerable theoretical and perhaps therapeutic interest.
|
Acknowledgments
|
|---|
We are indebted to Jean Ann Gilder for editing the text.
|
Footnotes
|
|---|
This study was supported in part by Grant Ministero dell’Università e della Ricerca Scientifica e Tecnologica (cofinanced project, year 2000) No. M06263471-005.
Abbreviations: ECG, Electrocardiogram; rhTSH, recombinant human TSH.
Received April 5, 2002.
Accepted October 15, 2002.
|
References
|
|---|
- Mazzaferri EL, Jhiang SM 1994 Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418–428[CrossRef][Medline]
- Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG 1996 Treatment guidelines for patients with thyroid nodules and well differentiated thyroid cancer. Arch Inter Med 156:2165–2172[Abstract]
- Solomon L, Wartofsky L, Burman KD 1996 Current trends in the management of well differentiated thyroid carcinoma. J Clin Endocrinol Metab 81:333–339[Abstract]
- Schlumberger MJ 1998 Papillary and follicular thyroid carcinoma. N Engl J Med 338:297–306[Free Full Text]
- Pacini F, Lari R, Mazzeo S, Grasso L, Taddei D, Pinchera A 1985 Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol (Oxf) 23:405–411[Medline]
- Maxon III HR, Smith HS 1980 Radioiodine-131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer. Endocrinol Metab Clin North Am 19:685–718
- Wieshammer S, Keck FS, Waitzinger J, Kohler J, Adam W, Stauch M, Pfeiffer EF 1988 Left ventricular function at rest and during exercise in acute hypothyroidism. Br Heart J 60:204–211[Abstract/Free Full Text]
- Fazio S, Biondi B, Lupoli G, Cittadini A, Santomauro M, Tommaselli AP, Lombardi G, Sacca L 1992 Evaluation by noninvasive method of the effects of acute loss of thyroid hormone on the heart. Angiology 43:287–293
- Grossmann G, Wieshammer S, Keck FS, Goller V, Giesler M, Hombach V 1994 Doppler echocardiographic evaluation of left ventricular diastolic function in acute hypothyroidism. Clin Endocrinol (Oxf) 40:227–233[Medline]
- Mohr-Kahaly S, Kahaly G, Konig P 1994 Cardiac function in short-term hypothyroidism. In: Braverman LE, Eber O, Langsteger W, eds. Heart and thyroid. Wien, Austria: Blackwell MZV; 147–149
- Weissel M, Punzengruber C 1994 Influence of L-thyroxine replacement therapy on cardiac function of athyreotic thyroid cancer patients. An echophonocardiographic study. In: Braverman LE, Eber O, Langsteger W, eds. Heart and thyroid. Wien, Austria: Blackwell MZV; 147–149
- Bengel FM, Nekolla SG, Ibrahim T, Weniger C, Ziegler I, Schwaiger M 2000 Effect of thyroid hormones on cardiac function, geometry and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging. J Clin Endocrinol Metab 85:1822–1827[Abstract/Free Full Text]
- Meier CA, Braverman LE, Ebner SA, Veronikis I, Daniels GH, Ross DS, Deraska DJ, Davies TF, Valentine M, DeGroot LJ, Curran P, McEllin K, Reynolds J, Robbins J, Weintraub BD 1994 Diagnostic use of recombinant human throtropin in patients with thyroid carcinoma (phase I/II study). J Clin Endocrinol Metab 78:188–196[Abstract]
- Ladenson PW, Braverman LE, Mazzaferri EL, Brucker-Davis F, Cooper DS, Garber JR, Wondisford FE, Davies TF, DeGroot LJ, Daniels GH, Ross DS, Weintraub BD 1997 Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid administration for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 337:888–896[Abstract/Free Full Text]
- Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon 3rd HR, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC 1999 A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 84:3877–3885[Abstract/Free Full Text]
- Down KH, Ferrell BR, Anello C 1997 Quality of life changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy. Thyroid 7:613–619[Medline]
- Drvota V, Janson A, Norman C, Sylven C, Haggblad J, Bronnegard M, Marcus C 1995 Evidence for the presence of functional thyrotropin receptor in cardiac muscle. Biochem Biophys Res Commun 211:426–431[CrossRef][Medline]
- Koshiyama H, Sellitti DF, Akamizu T, Doi SQ, Takeuchi Y, Inoue D, Sakaguchi H, Takemura G, Sato Y, Takatsu Y, Nakao K 1996 Cardiomiopathy associated with Grave’s disease. Clin Endocrinol (Oxf) 45:111–116[CrossRef][Medline]
- Sellitti DF, Hill R, Doi SQ, Akamizu T, Czaja J, Tao S, Koshiyama H 1996 Differential expression of thyrotropin receptor mRNA in the porcine heart. Thyroid 7:641–646
- Busuttil BE, Frauman AG 2001 Extrathyroidal manifestations of Graves’ disease: the thyrotropin receptor is expressed in extraocular, but not cardiac muscle tissues. J Clin Endocrinol Metab 86:2315–2319[Abstract/Free Full Text]
- Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, Sacca L, Bellastella A, Lombardi G 1993 Cardiac effects of long-term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 77:334–338[Abstract]
- Cittadini A, Fazio S, D’Ascia C, Basso A, Bazzicalupo L, Picardi G, Sacca L 1991 Subclinical cardiotoxicity by doxorubicin: a pulse Doppler echocardiographic study. Eur Heart J 12:1000–1005
- Sellitti DF, Doi SQ, Akamizu T, Koshiyama H 2002 Comment on "Thyrotropin receptor expression in cardiac muscle tissue." J Clin Endocrinol Metab 87:946[Free Full Text]
- Nagayama Y, Tanaka K, Hara T, Namba H, Yamashita S, Taniyama K, Niwa M 1996 Involvement of G protein-coupled receptor kinase 5 in homologous desensitization of the thyrotropin receptor. J Biol Chem 271:10143–10148[Abstract/Free Full Text]
- Sellitti DF, Dennison D, Akamazu T, Doi SQ, Kohn LD, Kashiyama B 2000 Thyrotropin regulation of cyclic adenosine monophosphate production in human coronary artery smooth muscle cells. Thyroid 10:219–225[Medline]
- Murray KJ 1990 Cyclic AMP and mechanisms of vasodilation. Pharmacol Ther 47:329–345[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
L. H Duntas and B. Biondi
Short-term hypothyroidism after Levothyroxine-withdrawal in patients with differentiated thyroid cancer: clinical and quality of life consequences
Eur. J. Endocrinol.,
January 1, 2007;
156(1):
13 - 19.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
