Central hypothyroidism associated with retinoid X receptor-selective ligands

Background The occurrence of symptomatic central hypothyroidism (characteri zed by low serum thyrotropin and thyroxine concentrations) in a patient wit h cutaneous T-cell lymphoma during therapy with the retinoid X receptor-sel ective ligand bexarotene led us to hypothesize that such ligands could reve rsibly suppress thyrotropin production by a thyroid hormone-independent mec hanism and thus cause central hypothyroidism. Methods We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one in stitution. in addition, we evaluated the in vitro effect of triiodothyronin e, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter. Results The mean serum thyrotropin concentration declined from 2.2 mU per l iter at base line to 0.05 mU per liter during treatment with bexarotene (P< 0.001), and the mean serum free thyroxine concentration declined from 1.0 n g per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with hig her doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Ninetee n patients had symptoms or signs of hypothyroidism, particularly fatigue an d cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin b eta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effec t similar to that of triiodothyronine and 9-cis-retinoic acid. Conclusions Hypothyroidism may develop in patients with cutaneous T-cell ly mphoma who are treated with high-dose bexarotene, most likely because the r etinoid X receptor-selective ligand suppresses thyrotropin secretion. (N En gl J Med 1999;340:1075-9.) (C) 1999, Massachusetts Medical Society.