Central hypothyroidism associated with retinoid X receptor-selective ligands

Area of Science:

• Endocrinology
• Oncology
• Pharmacology

Background:

• Central hypothyroidism characterized by low thyrotropin and thyroxine was observed in a patient with cutaneous T-cell lymphoma during bexarotene therapy.
• This led to the hypothesis that retinoid X receptor-selective ligands might suppress thyrotropin production independently of thyroid hormones.

Purpose of the Study:

• To investigate the effect of high-dose oral bexarotene on thyroid function in patients with cutaneous T-cell lymphoma.
• To evaluate the in vitro mechanism by which retinoid X receptor ligands influence thyrotropin gene promoter activity.

Main Methods:

• Thyroid function was assessed in 27 patients with cutaneous T-cell lymphoma receiving high-dose oral bexarotene.
• In vitro studies examined the impact of triiodothyronine, 9-cis-retinoic acid, and LGD346 on the thyrotropin beta-subunit gene promoter activity.

Main Results:

• Bexarotene treatment significantly reduced mean serum thyrotropin and free thyroxine levels (P<0.001).
• Higher bexarotene doses and prior interferon alfa treatment correlated with greater thyrotropin suppression.
• Nineteen patients experienced hypothyroidism symptoms, which resolved with thyroxine therapy and after discontinuing bexarotene. In vitro, LGD346 suppressed thyrotropin beta-subunit gene promoter activity.

Conclusions:

• High-dose bexarotene can induce hypothyroidism in cutaneous T-cell lymphoma patients, likely due to suppressed thyrotropin secretion.
• Retinoid X receptor-selective ligands are implicated in this mechanism.
• The observed hypothyroidism is reversible and manageable with standard thyroid hormone replacement therapy.