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

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.

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.