Objective: Therapy with the retinoid X receptor (RXR) agonist bexarotene is associated with hypothyroidism caused by decreased pituitary thyrotropin (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-thyroxine.

Design: Open prospective 6-weeks intervention study.

Methods: Ten athyreotic patients with pulmonary metastases of differentiated thyroid carcinoma received 6-week redifferentiation treatment with 300 mg bexarotene/day. L-thyroxine doses were kept stable. Before and in the 6^th week of therapy, serum levels of total tetraiodothyronine (T4), free-T4 (FT4), triodothyronine (T3), reverse T3 (rT3) and TSH were measured. To study non-deiodinase mediated thyroid hormone degradation, serum levels of sulphated T4 (T4S) were measured. Recombinant human TSH (rhTSH) was administered before and the 6^th 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 rhTSH were unaffected by bexarotene.

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