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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2822
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2496-2499
Copyright © 2007 by The Endocrine Society

Bexarotene-Induced Hypothyroidism: Bexarotene Stimulates the Peripheral Metabolism of Thyroid Hormones

Johannes W. A. Smit, Marcel P. M. Stokkel, Alberto M. Pereira, Johannes A. Romijn and Theo J. Visser

Departments of Endocrinology (J.W.A.S., A.M.P., J.A.R.) and Nuclear Medicine (M.P.M.S.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Internal Medicine (T.J.V.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Johannes W. A. Smit, M.D., Ph.D., Department of Endocrinology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: jwasmit{at}lumc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Therapy with the retinoid X receptor agonist bexarotene is associated with hypothyroidism caused by decreased pituitary TSH secretion. To evaluate the effects of bexarotene on peripheral thyroid hormone metabolism, we performed a study in athyreotic subjects on a fixed substitution dose with L-T4.

Design: The design was an open prospective 6-wk intervention study.

Methods: Ten athyreotic patients with pulmonary metastases of differentiated thyroid carcinoma received 6-wk redifferentiation treatment with 300 mg bexarotene/d. L-T4 doses were kept stable. Before and in the sixth week of therapy, serum levels of total T4, free T4 (FT4), T3, reverse T3 (rT3), and TSH were measured. To study nondeiodinase-mediated thyroid hormone degradation, serum levels of T4 sulfate (T4S) were measured. Recombinant human TSH was administered before and in the sixth week of bexarotene therapy.

Results: Bexarotene induced profound decreases in total T4 (56% of baseline), FT4 (47%), T3 (69%), rT3 (51%), and T4S (70%) in all patients, whereas TSH levels were not affected. The T3/rT3 ratio increased by 43%, and the T4S/FT4 ratio increased by 48%. Serum TSH levels before and after recombinant human TSH were unaffected by bexarotene.

Conclusions: In the present study, we demonstrate that increased peripheral degradation of thyroid hormones by a nondeiodinase-mediated pathway contributes to bexarotene induced-hypothyroidism.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
RETINOIDS ARE DERIVATIVES of vitamin A (i.e. retinol). Retinoid receptors belong to the family of nuclear receptors and can be distinguished in retinoic acid receptors and retinoid X receptors. Bexarotene (Targretin; Ligand Pharmaceuticals, San Diego, CA) is an retinoid X receptor-selective retinoid that has been approved by the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for treatment of cutaneous T cell lymphoma (1). Bexarotene is also investigated for other malignancies, including thyroid carcinoma (2). In addition, bexarotene also has effects on metabolic pathways such as insulin sensitivity (3).

Therapy with bexarotene is accompanied by central hypothyroidism (4). Experimental studies have revealed that the rexinoid LG268 suppresses TSH promoter activity, TSH mRNA synthesis, and TSH secretion, whereas no effect on TRH synthesis was observed (5). A study with LG100268 demonstrated an effect on TSH secretion, independently of TSH ß-gene expression (6). In a study in human volunteers, a single dose of bexarotene decreased serum TSH, T4, and T3 levels (7). In addition to these observations, experimental studies have also suggested that rexinoids may influence peripheral thyroid hormone metabolism through increased (5) or decreased (8) type 1 deiodinase activity or by the induction of hepatic detoxification enzymes, which may constitute a nondeiodinase mechanism of thyroid hormone metabolism (9).

No human studies have been published to address the effects of bexarotene on peripheral thyroid hormone metabolism. We therefore studied the effects of bexarotene, administered for 6 wk, on peripheral thyroid hormone metabolism in athyreotic humans with stable thyroid hormone substitution.


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

The effects of bexarotene on peripheral thyroid hormone metabolism were studied in athyreotic patients with non-iodine accumulating pulmonary metastases of differentiated thyroid carcinoma who received 6-wk open therapy with 300 mg/d bexarotene to achieve reinduction of iodine uptake. This study has been published previously (2). Exclusion criteria were pregnancy, contraindications for the application of recombinant human TSH (rhTSH), and contraindications for the use of bexarotene. The institutional review board approved the study, and all patients gave written informed consent.

The patients were treated with 300 mg/d bexarotene at the evening meal to prevent interference with L-T4 absorption. Before bexarotene and in the last week of bexarotene therapy, the patients received two injections of 0.9 mg rhTSH (Thyrogen; Genzyme, Naarden, The Netherlands) on 2 consecutive days. Blood was taken for thyroglobulin and TSH measurements 48 and 96 h after the first rhTSH injection. Patients visited the hospital every week for a physical examination and assessment of laboratory parameters. Fasting morning blood samples were taken and stored at –80 C until analysis.

Laboratory parameters

The following laboratory parameters were assessed: serum TSH, total T4, free T4 (FT4), total T3, and reverse T3 (rT3). T4 sulfate (T4S) was measured as a marker for T4 degradation.

Safety parameters were a hematological profile, serum levels of sodium, potassium and creatinine, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, hemoglobin-A1c concentration, alanine aminotransferase, aspartate aminotransferase, {gamma}-glutamyltransferase, alkaline phosphatase, and lactate dehydrogenase. They were assessed every week.

Analyses

TSH, FT4, T4, and T3 were measured by chemiluminescence assays (Vitros ECI Immunodiagnostic System; Ortho-Clinical Diagnostics, Rochester, NY). rT3 was measured with an in-house RIA (10). T4S was prepared by the method of Eelkman Rooda et al. (11). Serum T4S was measured using a specific antibody, as described previously (12). The detection limit of the TSH assay was 0.005 mU/liter. Within-assay coefficients of variation amounted to 4% for TSH, 2% for T4, 2% for T3, 3–4% for rT3, and 6–17% for T4S.

Statistical methods

Data are reported as mean ± SD. The effects of bexarotene on outcome variables were analyzed using the two-tailed Student’s t test for paired data. Data without normal distribution were analyzed using the Wilcoxon’s test. Differences were considered statistically significant at P < 0.05. The calculations were performed using SPSS 12.0 for windows (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients

Twelve patients were included in the protocol. One patient underwent acute surgery for intestinal volvulus. The data of this patient were not included in the analyses. From another patient, baseline blood samples were missing, so 10 patients were included in the analysis. Their clinical characteristics are presented in Table 1Go. All patients were in a good physical condition (eight patients had Karnofsky score 0; two patients had score 1). Two patients had well-controlled type 2 diabetes mellitus. Three patients had a history of hypercholesterolemia, which was treated with cholesterol synthesis inhibitors. Two patients had well-controlled hypertension, one patient had well-controlled ischemic heart disease, and one patient had obstructive pulmonary disease.


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  		TABLE 1. Patient data

 
The patients tolerated the bexarotene treatment well. In one patient (patient 3), the dose had to be reduced to 150 mg/d because of hypertriglyceridemia that stabilized after dose reduction. One patient (patient 1) experienced an episode of leucopenia, which also led to a dose reduction of bexarotene (150 mg/d). During treatment with bexarotene, the L-T4 dose was kept stable (188 ± 43 µg/d). The study results with respect to radioiodine uptake have been published previously (2).

Biochemical parameters

A significant increase in serum levels of total cholesterol (5.4 ± 1.0 to 7.8 ± 1.2 mmol/liter; P <0.001), triglycerides (1.6 ± 0.7 to 3.7 ± 1.5 mmol/liter; P < 0.001), and low-density lipoprotein cholesterol (3.6 ± 0.6 to 5.1 ± 0.3 mmol/liter; P < 0.001) was observed. High-density lipoprotein cholesterol was unaffected (1.7 ± 0.4 and 1.3 ± 0.5 mmol/liter; P = 0.374). No differences were observed in serum glucose levels (5.7 ± 1.0 and 5.3 ± 0.3 mmol/liter; P = 0.241) and hemoglobin A1c concentration (5.1 ± 0.5 and 5.2 ± 0.5%; P = 0.235). Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, {gamma}-glutamyltransferase, lactate dehydrogenase, creatinine, and electrolytes were not influenced by bexarotene therapy as well.

Thyroid hormone-related parameters

Thyroid hormone-related parameters are given in Table 2Go. Significant and profound decreases in total T4 (56 ± 11% of baseline), FT4 (47 ± 14%), T3 (69 ± 11%), and rT3 (51 ± 14%) were observed in all patients. The T3/rT3 ratio, which is considered to be a sensitive indicator of the peripheral metabolism of thyroid hormone, increased by 43 ± 35%. Serum thyroid hormone-binding globulin levels remained unaltered. T4S decreased to 70 ± 23% of baseline after treatment with bexarotene. However, the T4S/FT4 ratio increased by 48% (P < 0.001).


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  		TABLE 2. Thyroid hormone-related parameters

 
Serum TSH levels were unaffected by bexarotene therapy (0.244 ± 0.681 mU/liter before bexarotene; 0.128 ± 0.328 mU/liter after bexarotene), despite the profound decrease in serum FT4 levels. rhTSH was administered before bexarotene and in the sixth week of bexarotene administration. TSH levels, 48 and 96 h after the first rhTSH injection, were not influenced by bexarotene (48 h, 173 ± 58 mU/liter before bexarotene vs. 194 ± 67 mU/liter after bexarotene; 96 h, 20 ± 10 vs. 22 ± 10 mU/liter; P = 0.684).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present investigation was conducted to study the contribution of altered peripheral metabolism of thyroid hormones to bexarotene-induced hypothyroidism. We found a profound and consistent TSH-independent decrease in the serum concentrations of total T4, T3, and FT4. Because the T4 dose was kept stable during the study, increased metabolism of thyroid hormones is the most likely explanation. The alternative explanation, that bexarotene had interfered with the intestinal absorption of L-T4 is unlikely, because the interval between bexarotene and L-T4 intake was approximately 12 h but cannot entirely ruled out.

Although central hypothyroidism through decreased TSH synthesis by bexarotene has been well established in experimental studies (5, 6, 13, 14) and in humans (4, 7), these studies could not exclude that altered peripheral metabolism of thyroid hormone could also contribute to bexarotene-induced hypothyroidism. Indeed, the net effects of bexarotene on peripheral metabolism of thyroid hormones can only be studied in athyreotic subjects. A 6-wk redifferentiation treatment protocol with 300 mg/d bexarotene in athyreotic thyroid carcinoma patients receiving stable L-T4 substitution therapy enabled us to address this issue.

Metabolism of thyroid hormones is mediated by iodothyronine deiodinases (D1, D2, and D3) (15) and by hepatic conjugating enzymes (9). Effects of rexinoids on deiodinases have been described in experimental studies: Machia et al. (8) observed decreased hepatic D1 activity, whereas Sharma et al. (5) found increased hepatic D1 activity. In other studies, the retinoids all-trans retinoic acid and 9-cis retinoic were found to stimulate D3 activity in different cell types but decreased D3 activity in neuroblastoma cells (16, 17).

The T3/rT3 ratio is considered to be a sensitive indicator of the peripheral metabolism of thyroid hormone, being positively influenced by D1 and D2 and negatively by D3. This ratio is also relatively independent of thyroidal T4 production and of variations in serum binding proteins. The parallel decreases in serum T4, T3, and rT3 levels and the modest increase in the T3/rT3 ratio in our study exclude major changes in D1, D2, or D3 activity by bexarotene. Therefore, the most likely explanation is increased degradation by other pathways than deiodination, such as hepatic conjugation mediated by UDP-glucuronyltransferases (18) and sulfotransferases (19). We assessed T4S as an indicator for the sulfation pathway. T4S decreased after treatment with bexarotene. However, the T4S/FT4 ratio increased by 48%, which may indeed indicate induction of T4 sulfation by bexarotene. It appears likely that glucuronidation of T4 is also increased by bexarotene, but this could not be investigated in our patients.

Serum TSH concentrations remained unaltered after 6-wk bexarotene despite the strong reduction in serum T4 and T3 levels, which indirectly confirms the suppressive effects of bexarotene on TSH secretion. Although serum TSH levels are known to remain low after prolonged TSH-suppressive L-T4 therapy, in a previous study, we found that an 18% decrease in serum FT4 levels over 4-wk in patients with prolonged TSH suppression induced a rise in TSH from 0.103 mU/liter at baseline to 2.285 mU/liter (20). We therefore believe that the absence of any TSH increase after a reduction in serum FT4 of more than 50% in our patients cannot be explained by sustained TSH suppression alone. The fact that TSH levels 48 and 96 h after rhTSH were comparable indicates that bexarotene does not influence TSH degradation or clearance.

In conclusion, in the present study, we demonstrated that increased peripheral degradation of thyroid hormones in addition to decreased TSH secretion contributes to bexarotene-induced hypothyroidism. In patients who develop hypothyroidism during bexarotene therapy, it should be realized that TSH measurements are unreliable to monitor L-T4 substitution therapy and that higher L-T4 dosages may be required than expected because of the enhanced degradation of thyroid hormones.


   Footnotes
 
This research project was supported by a grant from the Dutch Cancer Foundation.

Disclosure Statement: The authors have nothing to declare.

First Published Online April 17, 2007

Abbreviations: FT4, Free T4; rhTSH, recombinant human TSH; rT3, reverse T3; T4S, T4 sulfate.

Received December 20, 2006.

Accepted April 10, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Stadler R, Kremer A 2006 Therapeutic advances in cutaneous T-cell lymphoma (CTCL): from retinoids to rexinoids. Semin Oncol 33:S7–S10
  2. Liu YY, Stokkel MP, Pereira AM, Corssmit EP, Morreau HA, Romijn JA, Smit JW 2006 Bexarotene increases uptake of radioiodide in metastases of differentiated thyroid carcinoma. Eur J Endocrinol 154:525–531[Abstract/Free Full Text]
  3. Shulman AI, Mangelsdorf DJ 2005 Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med 353:604–615[Free Full Text]
  4. Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M 1999 Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 340:1075–1079[Abstract/Free Full Text]
  5. Sharma V, Hays WR, Wood WM, Pugazhenthi U, St.Germain DL, Bianco AC, Krezel W, Chambon P, Haugen BR 2006 Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis. Endocrinology 147:1438–1451[Abstract/Free Full Text]
  6. Liu S, Ogilvie KM, Klausing K, Lawson MA, Jolley D, Li D, Bilakovics J, Pascual B, Hein N, Urcan M, Leibowitz MD 2002 Mechanism of selective retinoid X receptor agonist-induced hypothyroidism in the rat. Endocrinology 143:2880–2885[Abstract/Free Full Text]
  7. Golden WM, Weber KB, Hernandez TL, Sherman SI, Woodmansee WW, Haugen BR 2007 Single-dose rexinoid rapidly and specifically suppresses serum thyrotropin in normal subjects. J Clin Endocrinol Metab 92:124–130[Abstract/Free Full Text]
  8. Macchia PE, Jiang P, Yuan YD, Chandarardna RA, Weiss RE, Chassande O, Samarut J, Refetoff S, Burant CF 2002 RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor. Am J Physiol Endocrinol Metab 283:E326–E331
  9. Howell SR, Shirley MA, Ulm EH 1998 Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid x receptor selectivity and effects on metabolic enzymes. Drug Metab Dispos 26:234–239[Abstract/Free Full Text]
  10. Visser TJ, Docter R, Hennemann G 1977 Radioimmunoassay of reverse tri-iodothyronine. J Endocrinol 73:395–396[Abstract/Free Full Text]
  11. Eelkman Rooda SJ, Kaptein E, van Loon MA, Visser TJ 1988 Development of a radioimmunoassay for triiodothyronine sulfate. J Immunoassay 9:125–134[Medline]
  12. Wu SY, Huang WS, Polk D, Florsheim WH, Green WL, Fisher DA 1992 Identification of thyroxine-sulfate (T4S) in human serum and amniotic fluid by a novel T4S radioimmunoassay. Thyroid 2:101–105[Medline]
  13. Breen JJ, Hickok NJ, Gurr JA 1997 The rat TSHß gene contains distinct response elements for regulation by retinoids and thyroid hormone. Mol Cell Endocrinol 131:137–146[CrossRef][Medline]
  14. Haugen BR, Brown NS, Wood WM, Gordon DF, Ridgway EC 1997 The thyrotrope-restricted isoform of the retinoid-X receptor-{gamma}1 mediates 9-cis-retinoic acid suppression of thyrotropin-ß promoter activity. Mol Endocrinol 11:481–489[Abstract/Free Full Text]
  15. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR 2002 Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89[Abstract/Free Full Text]
  16. Esfandiari A, Gagelin C, Gavaret JM, Pavelka S, Lennon AM, Pierre M, Courtin F 1994 Induction of type III-deiodinase activity in astroglial cells by retinoids. Glia 11:255–261[CrossRef][Medline]
  17. Kester MH, Kuiper GG, Versteeg R, Visser TJ 2006 Regulation of type III iodothyronine deiodinase expression in human cell lines. Endocrinology 147:5845–5854[Abstract/Free Full Text]
  18. de Sandro V, Catinot R, Kriszt W, Cordier A, Richert L 1992 Male rat hepatic UDP-glucuronosyltransferase activity toward thyroxine. Activation and induction properties—relation with thyroxine plasma disappearance rate. Biochem Pharmacol 43:1563–1569[CrossRef][Medline]
  19. Eelkman Rooda SJ, Kaptein E, Visser TJ 1989 Serum triiodothyronine sulfate in man measured by radioimmunoassay. J Clin Endocrinol Metab 69:552–556[Abstract/Free Full Text]
  20. Smit JW, Eustatia-Rutten CF, Corssmit EP, Pereira AM, Frolich M, Bleeker GB, Holman ER, van der Wall EE, Romijn JA, Bax JJ 2005 Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study. J Clin Endocrinol Metab 90:6041–6047[Abstract/Free Full Text]



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